436 results on '"Anthony H.V. Schapira"'
Search Results
2. Glucocerebrosidase-associated Parkinson disease: Pathogenic mechanisms and potential drug treatments
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Matthew E. Gegg, Elisa Menozzi, and Anthony H.V. Schapira
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Parkinson disease ,α-synuclein ,Lysosome ,Autophagy ,Lipid ,Neuroinflammation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Dysfunction of the endolysosomal system is implicated in the pathogenesis of both sporadic and familial Parkinson disease (PD). Variants in genes encoding lysosomal proteins have been estimated to be associated with more than half of PD cases. The most common genetic risk factor for PD are variants in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. In this review we will describe the clinical symptoms and pathology of GBA-PD, and how this might be affected by the type of GBA variant. The putative mechanisms by which GCase deficiency in neurons and glia might contribute to PD pathogenesis will then be discussed, with particular emphasis on the accumulation of α-synuclein aggregates and the spread of pathogenic α-synuclein species between the cell types. The dysregulation of not only sphingolipids, but also phospholipids and cholesterol in the misfolding of α-synuclein is reviewed, as are neuroinflammation and the interaction of GCase with LRRK2 protein, another important contributor to PD pathogenesis. Study of both non-manifesting GBA carriers and GBA-PD cohorts provides an opportunity to identify robust biomarkers for PD progression as well as clinical trials for potential treatments. The final part of this review will describe preclinical studies and clinical trials for increasing GCase activity or reducing toxic substrate accumulation.
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- 2022
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3. Ablation of the pro-inflammatory master regulator miR-155 does not mitigate neuroinflammation or neurodegeneration in a vertebrate model of Gaucher's disease
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Lisa Watson, Marcus Keatinge, Matthew Gegg, Qing Bai, M. Cosmin Sandulescu, Ayelet Vardi, Anthony H. Futerman, Anthony H.V. Schapira, Edward A. Burton, and Oliver Bandmann
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Neuroinflammation ,miR-155 ,Zebrafish ,Gaucher's disease ,Parkinson's disease ,Neurodegeneration ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Bi-allelic mutations in the glucocerebrosidase gene (GBA1) cause Gaucher's disease, the most common human lysosomal storage disease. We previously reported a marked increase in miR-155 transcript levels and early microglial activation in a zebrafish model of Gaucher's disease (gba1−/−). miR-155 is a master regulator of inflammation and has been implicated in a wide range of different neurodegenerative disorders. The observed miR-155 upregulation preceded the subsequent development of widespread pathology with marked neuroinflammation, closely resembling human Gaucher's disease pathology. We now report similar increases of miR-155 expression in mammalian models of GD, confirming that miR-155 upregulation is a shared feature in glucocerebrosidase (GCase) deficiency across different species. Using CRISPR/Cas9 mutagenesis we then generated a miR-155 mutant zebrafish line (miR-155−/−) with completely abolished miR-155 expression. Unexpectedly, loss of miR-155 did not mitigate either the reduced lifespan or the robust inflammatory phenotypes of gba1−/− mutant zebrafish. Our data demonstrate that neither neuroinflammation nor disease progression in GCase deficiency are dependent on miR-155 and suggest that miR-155 inhibition would not be a promising therapeutic target in Gaucher's disease.
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- 2019
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4. A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers
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Shi-Yu Yang, Michelle Beavan, Kai-Yin Chau, Jan-Willem Taanman, and Anthony H.V. Schapira
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neural crest stem cells ,Parkinson disease ,glucocerebrosidase ,α-synuclein ,chaperone ,PD modeling ,dopaminergic neurons ,GBA1 mutation ,ambroxol ,GBA1-associated PD ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Numerically the most important risk factor for the development of Parkinson's disease (PD) is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase) activity and are associated with increased α-synuclein levels, reflecting similar changes seen in idiopathic PD brain. We have developed a neural crest stem cell-derived dopaminergic neuronal model that recapitulates biochemical abnormalities in GBA1 mutation-associated PD. Cells showed reduced GCase protein and activity, impaired macroautophagy, and increased α-synuclein levels. Advantages of this approach include easy access to stem cells, no requirement to reprogram, and retention of the intact host genome. Treatment with a GCase chaperone increased GCase protein levels and activity, rescued the autophagic defects, and decreased α-synuclein levels. These results provide the basis for further investigation of GCase chaperones or similar drugs to slow the progression of PD.
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- 2017
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5. Mitochondrial dysfunction associated with glucocerebrosidase deficiency
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Matthew E. Gegg and Anthony H.V. Schapira
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Autophagy ,Gaucher disease ,Glucocerebrosidase ,Lysosome ,Mitochondria ,mitophagy ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The lysosomal hydrolase glucocerebrosidase (GCase) is encoded for by the GBA gene. Homozygous GBA mutations cause Gaucher disease (GD), a lysosomal storage disorder. Furthermore, homozygous and heterozygous GBA mutations are numerically the greatest genetic risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. The loss of GCase activity results in impairment of the autophagy‐lysosome pathway (ALP), which is required for the degradation of macromolecules and damaged organelles. Aberrant protein handling of α-synuclein by the ALP occurs in both GD and PD. α-synuclein is the principle component of Lewy bodies, a defining hallmark of PD. Mitochondrial dysfunction is also observed in both GD and PD. In this review we will describe how mitochondria are affected following loss of GCase activity. The pathogenic mechanisms leading to mitochondria dysfunction will also be discussed, focusing on the likely inhibition of the degradation of mitochondria by the ALP, also termed mitophagy. Other pathogenic cellular processes associated with GBA mutations that might contribute, such as the unfolding of GCase in the endoplasmic reticulum, calcium dysregulation and neuroinflammation will also be described. Impairment of the ALP and mitochondria dysfunction are common pathogenic themes between GD and PD and probably explain why GBA mutations increase the risk of developing PD that is very similar to sporadic forms of the disease.
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- 2016
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6. Resistance to the most common optic neuropathy is associated with systemic mitochondrial efficiency
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Gerassimos Lascaratos, Kai-Yin Chau, Haogang Zhu, Despoina Gkotsi, Rosalind King, Ivan Gout, Deborah Kamal, Philip J. Luthert, Anthony H.V. Schapira, and David F. Garway-Heath
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Neurodegeneration ,Glaucoma ,Intraocular pressure ,Mitochondria ,Ocular hypertension ,Normal tension glaucoma ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Glaucomatous optic neuropathy, an important neurodegenerative condition and the commonest optic neuropathy in humans, is the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with ageing and raised intraocular pressure (IOP). Using glaucomatous optic neuropathy as an exemplar for neurodegeneration, this study investigates putative factors imparting resistance to neurodegeneration. Systemic mitochondrial function, oxidative stress and vascular parameters were compared from isolated lymphocytes, whole blood and urine samples between 30 patients who have not developed the neuropathy despite being exposed for many years to very high IOP (‘resistant’), 30 fast deteriorating glaucoma patients despite having low IOP (‘susceptible’), and 30 age-similar controls. We found that ‘resistant’ individuals showed significantly higher rates of ADP phosphorylation by mitochondrial respiratory complexes I, II and IV, hyperpolarised mitochondrial membrane potential, higher levels of mitochondrial DNA, and enhanced capacity to deal with cytosolic calcium overload and exogenous oxidative stress, as compared to both controls and glaucoma patients. While it has been known for some years that mitochondrial dysfunction is implicated in neurodegeneration, this study provides a fresh perspective to the field of neurodegeneration by providing, for the first time, evidence that systemic mitochondrial efficiency above normal healthy levels is associated with an enhanced ability to withstand optic nerve injury. These results demonstrate the importance of cellular bioenergetics in glaucomatous disease progression, with potential relevance for other neurodegenerative disorders, and raise the possibility for new therapeutic targets in the field of neurodegeneration.
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- 2015
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7. Mitochondrial impairment increases FL-PINK1 levels by calcium-dependent gene expression
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Rubén Gómez-Sánchez, Matthew E. Gegg, José M. Bravo-San Pedro, Mireia Niso-Santano, Lydia Alvarez-Erviti, Elisa Pizarro-Estrella, Yolanda Gutiérrez-Martín, Alberto Alvarez-Barrientos, José M. Fuentes, Rosa Ana González-Polo, and Anthony H.V. Schapira
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SH-SY5Y ,CCCP ,Parkinson's disease ,PINK1 ,Calcium ,Mitophagy ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Mutations of the PTEN-induced kinase 1 (PINK1) gene are a cause of autosomal recessive Parkinson's disease (PD). This gene encodes a mitochondrial serine/threonine kinase, which is partly localized to mitochondria, and has been shown to play a role in protecting neuronal cells from oxidative stress and cell death, perhaps related to its role in mitochondrial dynamics and mitophagy. In this study, we report that increased mitochondrial PINK1 levels observed in human neuroblastoma SH-SY5Y cells after carbonyl cyanide m-chlorophelyhydrazone (CCCP) treatment were due to de novo protein synthesis, and not just increased stabilization of full length PINK1 (FL-PINK1). PINK1 mRNA levels were significantly increased by 4-fold after 24 h. FL-PINK1 protein levels at this time point were significantly higher than vehicle-treated, or cells treated with CCCP for 3 h, despite mitochondrial content being decreased by 29%. We have also shown that CCCP dissipated the mitochondrial membrane potential (Δψm) and induced entry of extracellular calcium through L/N-type calcium channels. The calcium chelating agent BAPTA-AM impaired the CCCP-induced PINK1 mRNA and protein expression. Furthermore, CCCP treatment activated the transcription factor c-Fos in a calcium-dependent manner. These data indicate that PINK1 expression is significantly increased upon CCCP-induced mitophagy in a calcium-dependent manner. This increase in expression continues after peak Parkin mitochondrial translocation, suggesting a role for PINK1 in mitophagy that is downstream of ubiquitination of mitochondrial substrates. This sensitivity to intracellular calcium levels supports the hypothesis that PINK1 may also play a role in cellular calcium homeostasis and neuroprotection.
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- 2014
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8. The remote assessment of parkinsonism supporting the ongoing development of interventions in Gaucher disease
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Micol Avenali, Marco Toffoli, Chiao-Yin Lee, Abigail Louise Higgins, Stephen Mullin, Fabio Blandini, Sofia Koletsi, and Anthony H.V. Schapira
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Pediatrics ,medicine.medical_specialty ,Gaucher Disease ,Parkinson's disease ,business.industry ,Parkinsonism ,Neurodegeneration ,Psychological intervention ,Prodromal Symptoms ,Parkinson Disease ,Disease ,medicine.disease ,Large cohort ,Parkinsonian Disorders ,Mutation ,Glucosylceramidase ,Humans ,Medicine ,Neurology (clinical) ,Genetic risk factor ,business ,Glucocerebrosidase - Abstract
Mutations in GBA which are causative of Gaucher disease in their biallelic form, are the most common genetic risk factor for Parkinson's disease (PD). The diagnosis of PD relies upon clinically defined motor features which appear after irreversible neurodegeneration. Prodromal symptoms of PD may provide a means to predict latent pathology, years before the onset of motor features. Previous work has reported prodromal features of PD in GBA mutation carriers, however this has been insufficiently sensitive to identify those that will develop PD. The Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease (RAPSODI GD) study assesses a large cohort of GBA mutation carriers, to aid development of procedures for earlier diagnosis of PD.
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- 2021
9. Polygenic Parkinson’s disease genetic risk score as risk modifier of parkinsonism in Gaucher disease
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Cornelis Blauwendraat, Nahid Tayebi, Elizabeth Geena Woo, Grisel Lopez, Luca Fierro, Marco Toffoli, Naomi Limbachiya, Derralynn Hughes, Vanessa Pitz, Dhairya Patel, Dan Vitale, Mathew J. Koretsky, Dena Hernandez, Raquel Real, Roy N. Alcalay, Mike A. Nalls, Huw R. Morris, Anthony H.V. Schapira, Manisha Balwani, and Ellen Sidransky
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Neurology ,Neurology (clinical) - Abstract
BackgroundBi-allelic pathogenic variants inGBA1are the cause of Gaucher disease (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. HeterozygousGBA1variants are also a common genetic risk factor for Parkinson’s disease (PD). GD manifests with considerable clinical heterogeneity and is also associated with an increased risk of PD.ObjectiveTo investigate the contribution of PD risk variants to risk of PD in patients with GD1.MethodsWe studied 225 patients with GD1, including 199 without PD and 26 with PD. All cases were genotyped and the genetic data was imputed using common pipelines.ResultsOn average, patients with GD1 with PD have a significantly higher PD genetic risk score than those without PD (P=0.021).ConclusionsOur results indicate that variants included in the PD genetic risk score were more frequent in patients with GD1 who developed PD, suggesting that common risk variants may affect underlying biological pathways.Supplemental datahere
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- 2022
10. Glucocerebrosidase 1 and leucine‐rich repeat kinase 2 in Parkinson disease and interplay between the two genes
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Elisa Menozzi, Anthony H.V. Schapira, Chiao-Yin Lee, and Kai-Yin Chau
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Kinase ,Neurodegeneration ,Golgi Apparatus ,Epistasis, Genetic ,Parkinson Disease ,GTPase ,Biology ,Leucine-rich repeat ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,medicine.disease ,Biochemistry ,LRRK2 ,nervous system diseases ,Cellular and Molecular Neuroscience ,Neuroprotective Agents ,Mediator ,rab GTP-Binding Proteins ,Cancer research ,medicine ,Animals ,Glucosylceramidase ,Humans ,Rab ,Glucocerebrosidase - Abstract
The glucocerebrosidase 1 gene (GBA1), bi-allelic variants of which cause Gaucher disease (GD), encodes the lysosomal enzyme glucocerebrosidase (GCase) and is a risk factor for Parkinson Disease (PD). GBA1 variants are linked to a reduction in GCase activity in the brain. Variants in Leucine-Rich Repeat Kinase 2 (LRRK2), such as the gain-of-kinase-function variant G2019S, cause the most common familial form of PD. In patients without GBA1 and LRRK2 mutations, GCase and LRRK2 activity are also altered, suggesting that these two genes are implicated in all forms of PD and that they may play a broader role in PD pathogenesis. In this review, we review the proposed roles of GBA1 and LRRK2 in PD, focussing on the endolysosomal pathway. In particular, we highlight the discovery of Ras-related in brain (Rab) guanosine triphosphatases (GTPases) as LRRK2 kinase substrates and explore the links between increased LRRK2 activity and Rab protein function, lysosomal dysfunction, alpha-synuclein accumulation and GCase activity. We also discuss the discovery of RAB10 as a potential mediator of LRRK2 and GBA1 interaction in PD. Finally, we discuss the therapeutic implications of these findings, including current approaches and future perspectives related to novel drugs targeting LRRK2 and GBA1.
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- 2021
11. Targeting the GBA1 pathway to slow Parkinson disease: Insights into clinical aspects, pathogenic mechanisms and new therapeutic avenues
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Elisa Menozzi, Marco Toffoli, and Anthony H.V. Schapira
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Pharmacology ,Pharmacology (medical) - Published
- 2023
12. Identification of pyrimidinyl piperazines as non-iminosugar glucocerebrosidase (GCase) pharmacological chaperones
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Tamaki Hoshikawa, Toru Watanabe, Makoto Kotake, Nathalie Tiberghien, Chi-kit Woo, Sian Lewis, Thomas Briston, Mumta Koglin, James M. Staddon, Ben Powney, Anthony H.V. Schapira, and Andrew K. Takle
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Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry - Published
- 2023
13. Enhancing the Activity of Glucocerebrosidase as a Treatment for Parkinson Disease
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Elisa Menozzi and Anthony H.V. Schapira
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Protein Folding ,Endoplasmic Reticulum ,Compound heterozygosity ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Animals ,Humans ,Genetic Predisposition to Disease ,Pharmacology (medical) ,Gene ,chemistry.chemical_classification ,Endoplasmic reticulum ,Parkinson Disease ,Small molecule ,030227 psychiatry ,Cell biology ,Psychiatry and Mental health ,Enzyme ,chemistry ,Mutation ,Disease Progression ,alpha-Synuclein ,Glucosylceramidase ,Neurology (clinical) ,Psychopharmacology ,Glucocerebrosidase ,030217 neurology & neurosurgery - Abstract
Mutations in the glucocerebrosidase (GBA1) gene are the most common genetic risk factor for Parkinson disease (PD). Homozygous or compound heterozygous GBA1 mutations cause the lysosomal storage disorder Gaucher disease (GD), characterized by deficient activity of the glucocerebrosidase enzyme (GCase). Both individuals with GD type I and heterozygous carriers of pathogenic variants of GBA1 have an increased risk of developing PD, by approximately ten- to 20-fold compared to non-carriers. GCase activity is also reduced in PD patients without GBA1 mutations, suggesting that the GCase lysosomal pathway might be involved in PD pathogenesis. Available evidence indicates that GCase can affect α-synuclein pathology in different ways. Misfolded GCase proteins are retained in the endoplasmic reticulum, altering the lysosomal trafficking of the enzyme and disrupting protein trafficking. Also, deficient GCase leads to accumulation of substrates that in turn may bind α-synuclein and promote pathological formation of aggregates. Furthermore, α-synuclein itself can lower the enzymatic activity of GCase, indicating that a bidirectional interaction exists between GCase and α-synuclein. Targeted therapies aimed at enhancing GCase activity, augmenting the trafficking of misfolded GCase proteins by small molecule chaperones, or reducing substrate accumulation, have been tested in preclinical and clinical trials. This article reviews the molecular mechanisms linking GCase to α-synuclein and discusses the therapeutic drugs that by targeting the GCase pathway can influence PD progression.
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- 2020
14. Glucocerebrosidase deficiency promotes release of α-synuclein fibrils from cultured neurons
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Guglielmo Verona, Matthew E. Gegg, and Anthony H.V. Schapira
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AcademicSubjects/SCI01140 ,0301 basic medicine ,Aging ,Synucleinopathies ,animal diseases ,Endogeny ,Biology ,medicine.disease_cause ,environment and public health ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Autophagy ,Genetics ,medicine ,Animals ,Humans ,heterocyclic compounds ,Phosphorylation ,Cognitive decline ,Molecular Biology ,Genetics (clinical) ,Neurons ,Mutation ,Gaucher Disease ,Brain ,Parkinson Disease ,General Medicine ,nervous system diseases ,Cell biology ,Glucosylceramidase ,Disease Models, Animal ,030104 developmental biology ,nervous system ,alpha-Synuclein ,Unfolded protein response ,General Article ,Lysosomes ,Glucocerebrosidase ,030217 neurology & neurosurgery - Abstract
Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the most important genetic risk factor for Parkinson disease (PD). GCase activity is also decreased in sporadic PD brains and with normal ageing. Loss of GCase activity impairs the autophagy lysosomal pathway resulting in increased α-synuclein (α-syn) levels. Furthermore, elevated α-syn results in decreased GCase activity. Although the role of α-syn in PD remains unclear, evidence indicates that aggregated α-syn fibrils are a pathogenic species in PD, passing between neurons and inducing endogenous native α-syn to aggregate; spreading pathology through the brain. We have investigated if preformed α-syn fibrils (PFFs) impair GCase activity in mouse cortical neurons and differentiated dopaminergic cells, and whether GCase deficiency in these models increased the transfer of α-syn pathology to naïve cells. Neurons treated with PFFs induced endogenous α-syn to become insoluble and phosphorylated at Ser129 to a greater extent than monomeric α-syn-treatment. PFFs, but not monomeric α-syn, inhibited lysosomal GCase activity in these cells and induced the unfolded protein response. Neurons in which GCase was inhibited by conduritol β-epoxide did not increase the amount of insoluble monomeric α-syn or its phosphorylation status. Instead the release of α-syn fibrils from GCase deficient cells was significantly increased. Co-culture studies showed that the transfer of α-syn pathology to naïve cells was greater from GCase deficient cells. This study suggests that GCase deficiency increases the spread of α-syn pathology and likely contributes to the earlier age of onset and increased cognitive decline associated with GBA-PD.
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- 2020
15. Biofluid Biomarkers in Parkinson's Disease: Clarity Amid Controversy
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Marco Toffoli, Philip Campbell, Anthony H.V. Schapira, and Sophia R.L. Vieira
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Alpha-synuclein ,Oncology ,medicine.medical_specialty ,Parkinson's disease ,business.industry ,Parkinson Disease ,medicine.disease ,Prodrome ,Oxidative Stress ,chemistry.chemical_compound ,Blood ,Neurology ,chemistry ,Internal medicine ,alpha-Synuclein ,medicine ,Glucosylceramidase ,Humans ,Biomarker (medicine) ,Neurology (clinical) ,business ,Glucocerebrosidase ,Biomarkers ,Cerebrospinal Fluid - Published
- 2020
16. Comprehensive analysis of GBA using a novel algorithm for Illumina whole-genome sequence data or targeted Nanopore sequencing
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Monica Emili Garcia-Segura, Sonja W. Scholz, Fritz J. Sedlazeck, Xiao Chen, Marco Toffoli, Chiao-Yin Lee, Stephen Mullin, Esther Sammler, Anthony H.V. Schapira, Christos Proukakis, Michael A. Eberle, Abigail Louise Higgins, and Sofia Koletsi
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Whole genome sequencing ,medicine.diagnostic_test ,Pseudogene ,medicine ,Copy-number variation ,Nanopore sequencing ,Gene conversion ,Computational biology ,Biology ,Allele ,Illumina dye sequencing ,Genetic testing - Abstract
GBA variants cause the autosomal recessive Gaucher disease, and carriers are at increased risk of Parkinson’s disease (PD) and Lewy body dementia (LBD). The presence of a highly homologous nearby pseudogene (GBAP1) predisposes to a range of structural variants arising from either gene conversion or reciprocal recombination, the latter resulting in copy number gains or losses, complicating genetic testing and analysis. To date, short-read sequencing has not been able to fully resolve these or other variants in the key homology region, and targeted long-read sequencing has not previously resolved reciprocal recombinants. We present and validate two independent methods to resolve recombinant alleles and other variants in GBA: Gauchian, a novel bioinformatics tool for short-read, whole-genome sequencing data analysis, and Oxford Nanopore long-read sequencing after enrichment with appropriate PCR. The methods were concordant for 42 samples including 30 with a range of recombinants and GBAP1-related mutations, and Gauchian outperforms the GATK Best Practices pipeline. Applying Gauchian to Illumina sequencing of over 10,000 individuals from publicly available cohorts shows that copy number variants (CNVs) spanning GBAP1 are relatively common in Africans. CNV frequencies in PD and LBD are similar to controls, but gains may coexist with other mutations in patients, and a modifying effect cannot be excluded. Gauchian detects a higher frequency of GBA variants in LBD than PD, especially severe ones. These findings highlight the importance of accurate GBA mutation detection in these patients, which is possible by either Gauchian analysis of short-read whole genome sequencing, or targeted long-read sequencing.
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- 2021
17. A multinational consensus on dysphagia in Parkinson's disease:screening, diagnosis and prognostic value
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Enrico Alfonsi, Maggie-Lee Huckabee, Giovanni Abbruzzese, Marco Benazzo, Shaheen Hamdy, Leonardo Lopiano, Pietro Cortelli, Chiara Ferrari, Fabrizio Stocchi, Cristina Montomoli, Rosario Marchese Ragona, Francesca Valentino, Giovanni Ruoppolo, Anthony H.V. Schapira, Filippo Barbiera, Roberto Eleopra, Mariangela Rondanelli, Nicole Pizzorni, Giuseppe Cosentino, Cristina Tassorelli, Antonio Schindler, Giorgio Sandrini, Ronald F. Pfeiffer, Angelo Antonini, Emilia Michou, Claudio Pacchetti, Antonio Occhini, Pere Clavé, Domenico A. Restivo, Mauro Zamboni, Stefano Masiero, Roberta Zangaglia, Eduardo Tolosa, Mario Zappia, Micol Avenali, Giulia Bertino, Eduardo Elias Benarroch, Emanuele Cereda, Cosentino G., Avenali M., Schindler A., Pizzorni N., Montomoli C., Abbruzzese G., Antonini A., Barbiera F., Benazzo M., Benarroch E.E., Bertino G., Cereda E., Clave P., Cortelli P., Eleopra R., Ferrari C., Hamdy S., Huckabee M.-L., Lopiano L., Marchese Ragona R., Masiero S., Michou E., Occhini A., Pacchetti C., Pfeiffer R.F., Restivo D.A., Rondanelli M., Ruoppolo G., Sandrini G., Schapira A.H.V., Stocchi F., Tolosa E., Valentino F., Zamboni M., Zangaglia R., Zappia M., Tassorelli C., and Alfonsi E.
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medicine.medical_specialty ,Parkinson's disease ,Neurology ,dysphagia ,deglutition disorders ,swallowing disorders ,Clinical Neurology ,Deglutition disorders ,Dysphagia ,Swallowing disorders ,Deglutition ,Humans ,Italy ,Prognosis ,Quality of Life ,Deglutition Disorders ,Parkinson Disease ,Disease ,PHARYNGEAL DYSPHAGIA ,Severity assessment ,Quality of life ,QUALITY-OF-LIFE ,MANOMETRIC ABNORMALITIES ,medicine ,otorhinolaryngologic diseases ,Intensive care medicine ,ASPIRATION PNEUMONIA ,Deglutition disorder ,Neuroradiology ,Science & Technology ,CLINICAL-ASSESSMENT ,business.industry ,Consensus conference ,OROPHARYNGEAL DYSPHAGIA ,medicine.disease ,DYSFUNCTION ,PENETRATION-ASPIRATION ,Neurosciences & Neurology ,Neurology (clinical) ,medicine.symptom ,business ,Life Sciences & Biomedicine ,VOLUNTARY COUGH - Abstract
Background Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a combination of motor and non-motor dysfunction. Dysphagia is a common symptom in PD, though it is still too frequently underdiagnosed. Consensus is lacking on screening, diagnosis, and prognosis of dysphagia in PD. Objective To systematically review the literature and to define consensus statements on the screening and the diagnosis of dysphagia in PD, as well as on the impact of dysphagia on the prognosis and quality of life (QoL) of PD patients. Methods A multinational group of experts in the field of neurogenic dysphagia and/or PD conducted a systematic revision of the literature published since January 1990 to February 2021 and reported the results according to PRISMA guidelines. The output of the research was then analyzed and discussed in a consensus conference convened in Pavia, Italy, where the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus. Results Eighty-five papers were used to inform the Panel’s statements even though most of them were of Class IV quality. The statements tackled four main areas: (1) screening of dysphagia: timing and tools; (2) diagnosis of dysphagia: clinical and instrumental detection, severity assessment; (3) dysphagia and QoL: impact and assessment; (4) prognostic value of dysphagia; impact on the outcome and role of associated conditions. Conclusions The statements elaborated by the Consensus Panel provide a framework to guide the neurologist in the timely detection and accurate diagnosis of dysphagia in PD.
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- 2021
18. The Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease – Study Protocol
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Sofia Koletsi, Fabio Blandini, Micol Avenali, Marco Toffoli, Stephen Mullin, Chiao-Yin Lee, Anthony H.V. Schapira, and Abigail Louise Higgins
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Oncology ,medicine.medical_specialty ,business.industry ,Parkinsonism ,Neurodegeneration ,Disease ,medicine.disease ,Penetrance ,Prodrome ,Hyposmia ,Internal medicine ,medicine ,Age of onset ,medicine.symptom ,Cognitive decline ,business - Abstract
Mutations in GBA which are causative of Gaucher disease in their biallelic form, are the most common genetic risk factor for Parkinson disease. The diagnosis of Parkinson disease relies upon clinically defined motor features which appear after irreversible neurodegeneration. Prodromal symptoms of Parkinson disease may provide a means to predict latent pathology, years before the onset of motor features. Previous work has reported prodromal features of Parkinson disease in GBA mutation carriers, however this has been insufficiently sensitive to identify those that will develop Parkinson disease. The Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease (RAPSODI) study assesses a large cohort of GBA mutation carriers, to aid development of procedures for earlier diagnosis of Parkinson disease.Summary PointsThe therapeutic focus for Parkinson disease is currently symptomatic, rather than disease-modifying or neuroprotective.Non-motor prodromal features of Parkinson disease may precede the motor symptoms required for clinical diagnosis by several years.GBA mutations, which are associated with Gaucher disease in their biallelic form, have emerged as the most common genetic risk factor for Parkinson Disease.GBA associated PD displays a slightly exaggerated phenotype, including earlier age of onset, enhanced cognitive decline, more severe affective disturbances, and a greater likelihood of manifesting REM Sleep Behaviour Disorder, hyposmia and autonomic dysfunction.The RAPSODI GD study is an annual remote assessment which aims to define the clinical prodrome of PD in a large cohort of GBA mutation carriers, to accurately predict clinical diagnosis.The secondary objectives of RAPSODI GD are to risk stratify homozygote and heterozygote GBA mutation carriers for PD risk, understand the variable penetrance of the GBA associated PD phenotype, and create a platform for the future evaluation of biomarkers of disease.The putative implication of the RAPSODI GD study is to contribute towards earlier diagnosis of GBA associated PD, to provide a timeframe for delivering neuroprotective interventions.Defining prodromal PD in GBA carriers may have wider implications for sporadic PD.
- Published
- 2021
19. Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers
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Anthony H.V. Schapira and Elisa Menozzi
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0301 basic medicine ,Parkinson's ,Disease ,Compound heterozygosity ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Allele ,RC346-429 ,Gene ,business.industry ,glucocerebrosidase ,medicine.disease ,Phenotype ,genotype-phenotype ,030104 developmental biology ,Neurology ,Immunology ,Biomarker (medicine) ,biomarker ,GBA ,Neurology (clinical) ,Neurology. Diseases of the nervous system ,business ,Glucocerebrosidase ,030217 neurology & neurosurgery ,Progressive disease - Abstract
Variants in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson disease (PD). These include pathogenic variants causing Gaucher disease (GD) (divided into “severe,” “mild,” or “complex”—resulting from recombinant alleles—based on the phenotypic effects in GD) and “risk” variants, which are not associated with GD but nevertheless confer increased risk of PD. As a group, GBA-PD patients have more severe motor and nonmotor symptoms, faster disease progression, and reduced survival compared with noncarriers. However, different GBA variants impact variably on clinical phenotype. In the heterozygous state, “complex” and “severe” variants are associated with a more aggressive and rapidly progressive disease. Conversely, “mild” and “risk” variants portend a more benign course. Homozygous or compound heterozygous carriers usually display severe phenotypes, akin to heterozygous “complex” or “severe” variants carriers. This article reviews genotype–phenotype correlations in GBA-PD, focusing on clinical and nonclinical aspects (neuroimaging and biochemical markers), and explores other disease modifiers that deserve consideration in the characterization of these patients.
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- 2021
20. Glucocerebrosidase mutations: A paradigm for neurodegeneration pathways
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Sophia R.L. Vieira and Anthony H.V. Schapira
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Alpha-synuclein ,Synucleinopathies ,Dementia with Lewy bodies ,Neurodegeneration ,Parkinson Disease ,Biology ,medicine.disease ,Compound heterozygosity ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Physiology (medical) ,Mutation ,Cancer research ,medicine ,Unfolded protein response ,alpha-Synuclein ,Glucosylceramidase ,Humans ,Lysosomes ,Glucocerebrosidase ,Neuroinflammation - Abstract
Biallelic (homozygous or compound heterozygous) glucocerebrosidase gene (GBA) mutations cause Gaucher disease, whereas heterozygous mutations are numerically the most important genetic risk factor for Parkinson disease (PD) and are associated with the development of other synucleinopathies, notably Dementia with Lewy Bodies. This phenomenon is not limited to GBA, with converging evidence highlighting further examples of autosomal recessive disease genes increasing neurodegeneration risk in heterozygous mutation carriers. Nevertheless, despite extensive research, the cellular mechanisms by which mutations in GBA, encoding lysosomal enzyme β-glucocerebrosidase (GCase), predispose to neurodegeneration remain incompletely understood. Alpha-synuclein (A-SYN) accumulation, autophagic lysosomal dysfunction, mitochondrial abnormalities, ER stress and neuroinflammation have been proposed as candidate pathogenic pathways in GBA-linked PD. The observation of GCase and A-SYN interactions in PD initiated the development and evaluation of GCase-targeted therapeutics in PD clinical trials.
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- 2021
21. A pragmatic, personalised approach to treatment initiation in Parkinson's disease
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Anthony H.V. Schapira
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medicine.medical_specialty ,Parkinson's disease ,business.industry ,MEDLINE ,Parkinson Disease ,medicine.disease ,Precision medicine ,Antiparkinson Agents ,Levodopa ,Text mining ,Humans ,Medicine ,Neurology (clinical) ,Precision Medicine ,business ,Intensive care medicine - Published
- 2020
22. Ablation of the pro-inflammatory master regulator miR-155 does not mitigate neuroinflammation or neurodegeneration in a vertebrate model of Gaucher's disease
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Oliver Bandmann, Edward A. Burton, Qing Bai, Matthew E. Gegg, Marcus Keatinge, M. Cosmin Sandulescu, Ayelet Vardi, Anthony H.V. Schapira, Anthony H. Futerman, and Lisa Watson
- Subjects
0301 basic medicine ,Parkinson's disease ,miR-155 ,lcsh:RC321-571 ,Animals, Genetically Modified ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Neuroinflammation ,Gaucher's disease ,medicine ,Lysosomal storage disease ,Animals ,Clustered Regularly Interspaced Short Palindromic Repeats ,Neurodegeneration ,Zebrafish ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Neurons ,Gaucher Disease ,biology ,medicine.disease ,biology.organism_classification ,Up-Regulation ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,Neurology ,Mutation ,Nerve Degeneration ,Disease Progression ,Cancer research ,Cytokines ,Encephalitis ,Glucosylceramidase ,Glucocerebrosidase ,030217 neurology & neurosurgery - Abstract
Bi-allelic mutations in the glucocerebrosidase gene (GBA1) cause Gaucher's disease, the most common human lysosomal storage disease. We previously reported a marked increase in miR-155 transcript levels and early microglial activation in a zebrafish model of Gaucher's disease (gba1-/-). miR-155 is a master regulator of inflammation and has been implicated in a wide range of different neurodegenerative disorders. The observed miR-155 upregulation preceded the subsequent development of widespread pathology with marked neuroinflammation, closely resembling human Gaucher's disease pathology. We now report similar increases of miR-155 expression in mammalian models of GD, confirming that miR-155 upregulation is a shared feature in glucocerebrosidase (GCase) deficiency across different species. Using CRISPR/Cas9 mutagenesis we then generated a miR-155 mutant zebrafish line (miR-155-/-) with completely abolished miR-155 expression. Unexpectedly, loss of miR-155 did not mitigate either the reduced lifespan or the robust inflammatory phenotypes of gba1-/- mutant zebrafish. Our data demonstrate that neither neuroinflammation nor disease progression in GCase deficiency are dependent on miR-155 and suggest that miR-155 inhibition would not be a promising therapeutic target in Gaucher's disease.
- Published
- 2019
23. The gut-brain axis and Parkinson disease: clinical and pathogenetic relevance
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Anthony H.V. Schapira, Elisa Menozzi, and Jane Macnaughtan
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Pathology ,medicine.medical_specialty ,Gastrointestinal Diseases ,Gut–brain axis ,microbiome ,Disease ,Review Article ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,α-synuclein ,Medicine ,Humans ,030212 general & internal medicine ,Microbiome ,Parkinson’s ,Gastrointestinal tract ,business.industry ,gut-brain axis ,Brain ,Parkinson Disease ,General Medicine ,Gastrointestinal Microbiome ,Gastrointestinal Tract ,Neurology ,Quality of Life ,α synuclein ,business - Abstract
Gastrointestinal disorders are one of the most significant non-motor problems affecting people with Parkinson disease (PD). Pathogenetically, the gastrointestinal tract has been proposed to be the initial site of pathological changes in PD. Intestinal inflammation and alterations in the gut microbiota may contribute to initiation and progression of pathology in PD. However, the mechanisms underlying this “gut-brain” axis in PD remain unclear. PD patients can display a large variety of gastrointestinal symptoms, leading to reduced quality of life and psychological distress. Gastrointestinal disorders can also limit patients’ response to medications, and consequently negatively impact on neurological outcomes. Despite an increasing research focus, gastrointestinal disorders in PD remain poorly understood and their clinical management often suboptimal. This review summarises our understanding of the relevance of the “gut-brain” axis to the pathogenesis of PD, discusses the impact of gastrointestinal disorders in patients with PD, and provides clinicians with practical guidance to their management.
- Published
- 2021
24. The lysosomotrope GPN mobilises Ca2+ from acidic organelles
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Anthony H.V. Schapira, Franz Bracher, Sandip Patel, Yu Yuan, Bethan S. Kilpatrick, Susanne Gerndt, and Christian Grimm
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Agonist ,medicine.drug_class ,Endoplasmic reticulum ,ATPase ,Bafilomycin ,Cell Biology ,Biology ,Ph changes ,chemistry.chemical_compound ,Cytosol ,medicine.anatomical_structure ,chemistry ,Lysosome ,Organelle ,medicine ,biology.protein ,Biophysics - Abstract
Lysosomes are acidic Ca2+ stores often mobilised in conjunction with endoplasmic reticulum (ER) Ca2+ stores. Glycyl-L-phenylalanine 2-naphthylamide (GPN) is a widely used lysosomotropic agent that evokes cytosolic Ca2+ signals in many cells. However, whether these signals are the result of a primary action on lysosomes is unclear in light of recent evidence showing that GPN mediates direct ER Ca2+ release through changes in cytosolic pH. Here, we show that GPN evoked rapid increases in cytosolic pH but slower Ca2+ signals. NH4Cl evoked comparable changes in pH but failed to affect Ca2+. The V-type ATPase inhibitor, bafilomycin A1, increased lysosomal pH over a period of hours. Acute treatment modestly affected lysosomal pH and potentiated Ca2+ signals evoked by GPN. In contrast, chronic treatment led to more profound changes in luminal pH and selectively inhibited GPN action. GPN blocked Ca2+ responses evoked by the novel nicotinic acid adenine dinucleotide phosphate-like agonist, TPC2-A1-N. Therefore, GPN-evoked Ca2+ signals were better correlated with associated pH changes in the lysosome compared to the cytosol, and were coupled to lysosomal Ca2+ release. We conclude that Ca2+ signals evoked by GPN most likely derive from acidic organelles.
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- 2021
25. Intronic Haplotypes in the GBA Gene Do Not Predict Age at Diagnosis of Parkinson's Disease
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Anthony H.V. Schapira, Chiao Lee, Fritz J. Sedlazeck, Xiao Chen, Abigail Louise Higgins, Sofia Koletsi, Michael A. Eberle, Christos Proukakis, Stephen Mullin, and Marco Toffoli
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,haplotypes ,Parkinson's disease ,Movement disorders ,Parkinson's ,Disease ,Regular Issue Articles ,intronic variants ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,genetics ,Risk factor ,Gene ,business.industry ,Parkinsonism ,Brief Report ,Haplotype ,Parkinson Disease ,medicine.disease ,Introns ,030104 developmental biology ,Neurology ,Cohort ,Mutation ,Glucosylceramidase ,Brief Reports ,GBA ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Background GBA mutations are a common risk factor for Parkinson's disease (PD). A recent study has suggested that GBA haplotypes, identified by intronic variants, can affect age at diagnosis of PD. Objectives In this study, we assess this hypothesis using long reads across a large cohort and the publicly available Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) cohort. Methods We recruited a PD cohort through the Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease study (RAPSODI) and sequenced GBA using Oxford Nanopore technology. Genetic and clinical data on the full AMP-PD cohort were obtained from the online portal of the consortium. Results A total of 1417 participants were analyzed. There was no significant difference in age at PD diagnosis between the two main haplotypes of the GBA gene. Conclusions GBA haplotypes do not affect age at diagnosis of PD in the two independent cohorts studied. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
- Published
- 2021
26. The PINK1-Parkin mitophagy signalling pathway is not functional in peripheral blood mononuclear cells
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Huw R. Morris, Philip Campbell, Jan-Willem Taanman, Anthony H.V. Schapira, and Aaron V. Bradshaw
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Physiology ,Mitochondrion ,Biochemistry ,Jurkat cells ,Parkin ,White Blood Cells ,Medical Conditions ,0302 clinical medicine ,Ubiquitin ,Animal Cells ,Mitophagy ,Medicine and Health Sciences ,MFN1 ,Post-Translational Modification ,Energy-Producing Organelles ,Connective Tissue Cells ,0303 health sciences ,Movement Disorders ,Multidisciplinary ,biology ,T Cells ,Chemistry ,Messenger RNA ,Neurodegenerative Diseases ,Parkinson Disease ,Mitochondria ,Cell biology ,Nucleic acids ,Electrophysiology ,Blot ,Neurology ,Connective Tissue ,Medicine ,Cellular Types ,Anatomy ,Cellular Structures and Organelles ,Research Article ,Signal Transduction ,Immune Cells ,Ubiquitin-Protein Ligases ,Science ,Immunology ,PINK1 ,Bioenergetics ,Peripheral blood mononuclear cell ,Membrane Potential ,03 medical and health sciences ,030304 developmental biology ,Blood Cells ,Ubiquitination ,Biology and Life Sciences ,Proteins ,Cell Biology ,Fibroblasts ,Biological Tissue ,Leukocytes, Mononuclear ,biology.protein ,RNA ,Mitochondrial Membrane ,030217 neurology & neurosurgery - Abstract
Mutations in the PINK1 and PRKN genes are the most common cause of early-onset familial Parkinson disease. These genes code for the PINK1 and Parkin proteins, respectively, which are involved in the degradation of dysfunctional mitochondria through mitophagy. An early step in PINK1 – Parkin mediated mitophagy is the ubiquitination of the mitofusin proteins MFN1 and -2. The ubiquitination of MFN1 and -2 in patient samples may therefore serve as a biomarker to determine the functional effects of PINK1 and PRKN mutations, and to screen idiopathic patients for potential mitophagy defects. We aimed to characterise the expression of the PINK1 – Parkin mitophagy machinery in peripheral blood mononuclear cells (PBMCs) and assess if these cells could serve as a platform to evaluate mitophagy via analysis of MFN1 and -2 ubiquitination. Mitophagy was induced through mitochondrial depolarisation by treatment with the protonophore CCCP and ubiquitinated MFN proteins were analysed by western blotting. In addition, PINK1 and PRKN mRNA and protein expression levels were characterised with reverse transcriptase quantitative PCR and western blotting, respectively. Whilst CCCP treatment led to MFN ubiquitination in primary fibroblasts, SH-SY5Y neuroblastoma cells and Jurkat leukaemic cells, treatment of PBMCs did not induce ubiquitination of MFN. PRKN mRNA and protein was readily detectable in PBMCs at comparable levels to those observed in Jurkat and fibroblast cells. In contrast, PINK1 protein was undetectable and PINK1 mRNA levels remarkably low in control PBMCs. Our findings suggest that the PINK1 – Parkin mitophagy signalling pathway is not functional in PBMCs. Therefore, PBMCs are not a suitable biosample for analysis of mitophagy function in Parkinson disease patients.
- Published
- 2021
27. Brain Microglial Activation Increased in Glucocerebrosidase (GBA) Mutation Carriers without Parkinson's disease
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D Hughes, Rainer Hinz, Anthony H.V. Schapira, Peter Parbo, Atul Mehta, Nicola Pavese, Stephen Mullin, David J. Brooks, and Morten Gersel Stokholm
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0301 basic medicine ,medicine.medical_specialty ,Parkinson's disease ,positron emission tomography ,microglia ,Substantia nigra ,Regular Issue Articles ,Gene mutation ,03 medical and health sciences ,0302 clinical medicine ,Hyposmia ,Dopamine ,Internal medicine ,medicine ,Humans ,Neuroinflammation ,business.industry ,glucocerebrosidase ,Brief Report ,Brain ,Parkinson Disease ,medicine.disease ,Penetrance ,030104 developmental biology ,Endocrinology ,Neurology ,substantia nigra ,Mutation ,Glucosylceramidase ,Brief Reports ,Neurology (clinical) ,medicine.symptom ,business ,Glucocerebrosidase ,030217 neurology & neurosurgery ,medicine.drug - Abstract
BackgroundGlucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls.MethodsWe performed PET scans on 9 glucocerebrosidase gene mutation carriers without Parkinson's disease and 29 age‐matched controls. We measured microglial activation as 11C‐(R)‐PK11195 binding potentials, and dopamine terminal integrity with 18F‐dopa influx constants.ResultsThe 11C‐(R)‐PK11195 binding potential was increased in the substantia nigra of glucocerebrosidase gene carriers compared with controls (Student t test; right, t = −4.45, P = 0.0001). Statistical parametric mapping also localized significantly increased 11C‐(R)‐PK11195 binding potential in the occipital and temporal lobes, cerebellum, hippocampus, and mesencephalon. The degree of hyposmia correlated with nigral 11C‐(R)‐PK11195 regional binding potentials (Spearman's rank, P = 0.0066). Mean striatal 18F‐dopa uptake was similar to healthy controls.ConclusionsIn vivo 11C‐(R)‐PK11195 PET imaging detects neuroinflammation in brain regions susceptible to Lewy pathology in glucocerebrosidase gene mutation carriers without Parkinson's. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
- Published
- 2020
28. Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation
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Donato A. Di Monte, Silvia Cerri, Anthony H.V. Schapira, Céline Galvagnion, and Fabio Blandini
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Ceramide ,Amyloid ,medicine.diagnostic_test ,Chemistry ,Lipid metabolism ,Shotgun lipidomics ,Sphingolipid ,chemistry.chemical_compound ,Biochemistry ,medicine ,lipids (amino acids, peptides, and proteins) ,Sphingomyelin ,Lipid profile ,Glucocerebrosidase - Abstract
Intraneuronal accumulation of aggregated α-synuclein is a pathological hallmark of Parkinson’s disease. Therefore, mechanisms capable of promoting α-synuclein deposition bear important pathogenetic implications. Mutations of the glucocerebrosidase 1 (GBA) gene represent a prevalent Parkinson’s disease risk factor. They are associated with loss of activity of a key enzyme involved in lipid metabolism, glucocerebrosidase, supporting a mechanistic relationship between abnormal α-synuclein-lipid interactions and the development of Parkinson pathology. In this study, the lipid membrane composition of fibroblasts isolated from control subjects, patients with idiopathic Parkinson’s disease (iPD) and Parkinson patients carrying the L444PGBAmutation (PD-GBA) was assayed using shotgun lipidomics. The lipid profile of PD-GBA fibroblasts differed significantly from that of control and iPD cells. It was characterized by an overall increase in sphingolipid levels. It also featured a significant change in the proportion of ceramide, sphingomyelin and hexosylceramide molecules with shorter and longer hydrocarbon chain length; levels of shorter-chain molecules were increased while the percent of longer-chain sphingolipids was decreased in PD-GBA lipid extracts. The extent of this shift was correlated to the degree of reduction of fibroblast glucocerebrosidase activity. In a second set of experiments, lipid extracts from control and PD-GBA fibroblasts were added to incubations of recombinant α-synuclein. The kinetics of α-synuclein aggregation, as assessed by the binding of thioflavin T to amyloid structures, was significantly accelerated after addition of PD-GBA extracts as compared to control samples. Amyloid fibrils collected at the end of these incubations contained lipids, indicating α-synuclein-lipid co-assembly. Lipids extracted from α-synuclein fibrils were also analysed by shotgun lipidomics. Data revealed that the lipid content of these fibrils was significantly enriched of shorter-chain sphingolipids. Taken together, findings of this study indicate that the L444PGBAmutation and consequent enzymatic loss are associated with a distinctly altered membrane lipid profile that provides a biological fingerprint of this mutation in Parkinson fibroblasts. This altered lipid profile, which includes an increased content of shorter-chain sphingolipids, could also be an indicator of increased risk for α-synuclein aggregate pathology. Shorter-chain molecules may act as preferred reactants during lipid-induced α-synuclein fibrillation.
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- 2020
29. Investigation of Somatic Mutations in Human Brains Targeting Genes Associated With Parkinson's Disease
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Christos Proukakis, Anthony H.V. Schapira, Melissa Leija-Salazar, Huw R. Morris, Alan Pittman, and Katya Mokretar
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0301 basic medicine ,Somatic cell ,Parkinson's disease ,Monozygotic twin ,Biology ,lcsh:RC346-429 ,03 medical and health sciences ,synuclein ,0302 clinical medicine ,Germline mutation ,molecular barcodes ,medicine ,somatic mutation ,targeted sequencing ,Allele frequency ,lcsh:Neurology. Diseases of the nervous system ,Original Research ,Genetics ,Synucleinopathies ,Lewy body ,Neurodegeneration ,synucleinopathies ,medicine.disease ,Penetrance ,LRRK2 ,030104 developmental biology ,Neurology ,SNCA ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
BackgroundSomatic mutations occur in neurons but their role in synucleinopathies is unknown.AimWe aimed to identify disease-relevant low-level somatic single nucleotide variants (SNVs) in brains from sporadic patients with synucleinopathies and a monozygotic twin carrying LRRK2 G2019S, whose penetrance could be explained by somatic variation.Methods and ResultsWe included different brain regions from 26 Parkinson’s disease (PD), 1 Incidental Lewy body, 3 multiple system atrophy cases and 12 controls. The whole SNCA locus and exons of other genes associated with PD and neurodegeneration were deeply sequenced using molecular barcodes to improve accuracy. We selected 21 variants at 0.33-5% allele frequencies for validation using accurate methods for somatic variant detection.ConclusionsWe could not detect disease-relevant somatic SNVs, however we cannot exclude their presence at earlier stages of degeneration. Our results support that coding somatic SNVs in neurodegeneration are rare, but other types of somatic variants may hold pathological consequences in synucleinopathies.
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- 2020
30. Acid Sphingomyelinase Deficiency Normalizes Neuronal Function in GCase Deficiency - Unexpected Biological Rescue Effect of Combined Genetic Risk Factors for Parkinson’s Disease
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Matthew E. Gegg, Oliver Bandmann, Marcus Keatinge, Anthony H.V. Schapira, Dirk Lefeber, Astrid van Rens, Lisa Watson, Ryan B. MacDonald, Heather Mortiboys, and Hai Bui
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Parkinson's disease ,business.industry ,Medicine ,Acid sphingomyelinase ,Genetic risk ,Bioinformatics ,business ,medicine.disease ,Function (biology) ,medicine.drug - Abstract
BackgroundThe additive mechanistic effect of genetic risk variants for Parkinson’s disease (PD) is a plausible but largely unproven hypothesis. We investigated the mechanistic interaction between the two lysosomal PD risk genes glucocerebrosidase 1 (GBA1) and sphingomyelinase 1 (SMPD1) in complementing model systems.MethodsUsing CRISPR/Cas gene editing, smpd1 mutant (smpd1-/-) zebrafish were generated and crossed to our previously characterised gba1-/- zebrafish line, generating double knockouts (gba1-/-;smpd1-/-). Spontaneous motor behaviour and survival were assessed in WT, single mutants and double mutants. HPLC-based sphingolipid quantification was combined with RNAseq based pathway analysis, assessment of the mitochondrial respiratory chain and quantification of lipid membrane oxidation for in-depth assessment of cellular health across all four genotypes. We also determined the effect of combined glucocerebrosidase (GCase) and acid sphingomyelinase (ASM) inactivation on autophagy and alpha-synuclein homeostasis in the human neuronal cell line SH-SY5Y.ResultsUnexpectedly, ASM deficiency rescued the marked behavioural phenotype and prolonged survival in gba1-/-;smpd1-/- double-mutant zebrafish compared to gba1-/-. RNAseq-based pathway analysis confirmed a profound rescue of neuronal function and intracellular homeostasis. We identified complete reciprocal rescue of mitochondrial respiratory chain function and abolished lipid membrane oxidation in gba1-/-;smpd1-/- compared to gba1-/- or smpd1-/- as the underlying rescue mechanism. The complementing in vitro experiments demonstrated an unexpected reduction of α-synuclein levels in human cell lines with combined GCase and ASM deficiency.ConclusionsOur study highlights the importance of functional validation for any putative mechanistic interactions between genetic risk factors and their overall effect on disease-relevant mechanisms rather than readily assuming an additive effect.
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- 2020
31. Functional assessment of glucocerebrosidase modulator efficacy in primary patient-derived macrophages is essential for drug development and patient stratification
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Matthew Butler, Mumta Koglin, Kavita Mistry, Malcolm Roberts, James M. Staddon, Ben Powney, Anthony H.V. Schapira, Christina A. Gewinner, Juniebel Cooke, and Natalie J. Welsh
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Primary (chemistry) ,Gaucher Disease ,business.industry ,Macrophages ,Hematology ,Molecular Pharmacology ,Bioinformatics ,Pharmacological chaperone ,Drug development ,Drug Development ,medicine ,Glucosylceramidase ,Humans ,business ,Online Only Articles ,Glucocerebrosidase ,Patient stratification ,medicine.drug - Published
- 2020
32. Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing
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Janice L. Holton, Anthony H.V. Schapira, Tammaryn Lashley, Hannah Franklin, Maxime Tarabichi, Melissa Leija-Salazar, George Vasmatzis, Christos Proukakis, Zane Jaunmuktane, Diego Perez-Rodriguez, Viorica Chelban, Maria Kalyva, Thomas T. Warner, Henry Houlden, Steve M. Gentleman, Lucia Schottlaender, and Multiple Sclerosis Society
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Male ,DNA Copy Number Variations ,Somatic cell ,Substantia nigra ,Biology ,Gyrus Cinguli ,lcsh:RC346-429 ,Pathology and Forensic Medicine ,Alpha-synuclein ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Germline mutation ,Neuromelanin ,Ecology,Evolution & Ethology ,mental disorders ,Humans ,Copy-number variation ,lcsh:Neurology. Diseases of the nervous system ,030304 developmental biology ,Computational & Systems Biology ,Synucleinopathies ,Genetics ,Neurons ,0303 health sciences ,Single cell sequencing ,Human Biology & Physiology ,Mosaicism ,Putamen ,Research ,Somatic mutation ,Brain ,Parkinson Disease ,Multiple system atrophy ,Tumour Biology ,nervous system diseases ,chemistry ,nervous system ,Parkinson’s disease ,Neurology (clinical) ,SNCA ,Single-Cell Analysis ,Genetics & Genomics ,030217 neurology & neurosurgery - Abstract
Synucleinopathies are mostly sporadic neurodegenerative disorders of partly unexplained aetiology, and include Parkinson’s disease (PD) and multiple system atrophy (MSA). We have further investigated our recent finding of somatic SNCA (α-synuclein) copy number variants (CNVs, specifically gains) in synucleinopathies, using Fluorescent in-situ Hybridisation for SNCA, and single-cell whole genome sequencing for the first time in a synucleinopathy. In the cingulate cortex, mosaicism levels for SNCA gains were higher in MSA and PD than controls in neurons (> 2% in both diseases), and for MSA also in non-neurons. In MSA substantia nigra (SN), we noted SNCA gains in > 3% of dopaminergic (DA) neurons (identified by neuromelanin) and neuromelanin-negative cells, including olig2-positive oligodendroglia. Cells with CNVs were more likely to have α-synuclein inclusions, in a pattern corresponding to cell categories mostly relevant to the disease: DA neurons in Lewy-body cases, and other cells in the striatonigral degeneration-dominant MSA variant (MSA-SND). Higher mosaicism levels in SN neuromelanin-negative cells may correlate with younger onset in typical MSA-SND, and in cingulate neurons with younger death in PD. Larger sample sizes will, however, be required to confirm these putative findings. We obtained genome-wide somatic CNV profiles from 169 cells from the substantia nigra of two MSA cases, and pons and putamen of one. These showed somatic CNVs in ~ 30% of cells, with clonality and origins in segmental duplications for some. CNVs had distinct profiles based on cell type, with neurons having a mix of gains and losses, and other cells having almost exclusively gains, although control data sets will be required to determine possible disease relevance. We propose that somatic SNCA CNVs may contribute to the aetiology and pathogenesis of synucleinopathies, and that genome-wide somatic CNVs in MSA brain merit further study.
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- 2020
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33. Somatic copy number gains of α-synuclein (SNCA) in Parkinson’s disease and multiple system atrophy brains
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Janice L. Holton, Anthony H.V. Schapira, Elizabeth Nacheva, Henry Houlden, Ayesha Ejaz, Katya Mokretar, Aynur Soenmez, Tammaryn Lashley, Helen Ling, Daniel Pease, Jan-Willem Taanman, Christos Proukakis, Steve M. Gentleman, and Multiple Sclerosis Society
- Subjects
Male ,0301 basic medicine ,Pathology ,Parkinson's disease ,Gene Expression ,SUREFISH DAKO OMNIS ,chemistry.chemical_compound ,0302 clinical medicine ,HUMAN GENOME ,somatic mutation ,Copy-number variation ,DNA-CONTENT VARIATION ,11 Medical and Health Sciences ,In Situ Hybridization, Fluorescence ,Comparative Genomic Hybridization ,Putamen ,Dopaminergic ,GENETIC-VARIATION ,Brain ,Parkinson Disease ,17 Psychology and Cognitive Sciences ,ALZHEIMERS-DISEASE ,Substantia Nigra ,alpha-Synuclein ,Female ,Life Sciences & Biomedicine ,HUMAN NEURONS ,medicine.medical_specialty ,DNA Copy Number Variations ,Clinical Neurology ,Substantia nigra ,Biology ,03 medical and health sciences ,SINGLE-CELL ,Atrophy ,medicine ,Humans ,Aged ,Synucleinopathies ,Alpha-synuclein ,Science & Technology ,Neurology & Neurosurgery ,MUTATIONS ,ANEUPLOIDY ,Dopaminergic Neurons ,Neurosciences ,Multiple System Atrophy ,medicine.disease ,NEURAL STEM/PROGENITOR CELLS ,mosaicism ,030104 developmental biology ,chemistry ,Neurosciences & Neurology ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
The α-synuclein protein, encoded by SNCA, has a key role in the pathogenesis of Parkinson's disease and other synucleinopathies. Although usually sporadic, Parkinson's disease can result from inherited copy number variants in SNCA and other genes. We have hypothesized a role of somatic SNCA mutations, leading to mosaicism, in sporadic synucleinopathies. The evidence for mosaicism in healthy and diseased brain is increasing rapidly, with somatic copy number gains of APP reported in Alzheimer's brain. Here we demonstrate somatic SNCA copy number gains in synucleinopathies (Parkinson's disease and multiple system atrophy), focusing on substantia nigra. We selected sporadic cases with relatively young onset or short disease duration, and first excluded high level copy number variant mosaicism by DNA analysis using digital PCR for SNCA, and/or customized array comparative genomic hybridization. To detect low level SNCA copy number variant mosaicism, we used fluorescent in situ hybridization with oligonucleotide custom-designed probes for SNCA, validated on brain and fibroblasts with known copy number variants. We determined SNCA copy number in nigral dopaminergic neurons and other cells in frozen nigra sections from 40 cases with Parkinson's disease and five with multiple system atrophy, and 25 controls, in a blinded fashion. Parkinson's disease cases were significantly more likely than controls to have any SNCA gains in dopaminergic neurons (P = 0.0036), and overall (P = 0.0052). The average proportion of dopaminergic neurons with gains in each nigra was significantly higher in Parkinson's disease than controls (0.78% versus 0.45%; P = 0.017). There was a negative correlation between the proportion of dopaminergic neurons with gains and onset age in Parkinson's disease (P = 0.013), but not with disease duration, or age of death in cases or controls. Cases with tremor at onset were less likely to have gains (P = 0.035). All multiple system atrophy cases had gains, and the highest levels in dopaminergic neurons were in two of these cases (2.76%, 2.48%). We performed selective validation with different probes after dye swapping. All three control probes used showed minimal or no gains (≤0.1% in dopaminergic neurons). We also found occasional SNCA gains in frontal neurons of cases with Parkinson's disease, and the putamen of one multiple system atrophy case. We present evidence of somatic SNCA gains in brain, more commonly in nigral dopaminergic neurons of Parkinson's disease than controls, negatively correlated with onset age, and possibly commonest in some multiple system atrophy cases. Somatic SNCA gains may be a risk factor for sporadic synucleinopathies, or a result of the disease process.10.1093/brain/awy157_video1awy157media15813519976001.
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- 2018
34. GYG1 causing progressive limb girdle myopathy with onset during teenage years (polyglucosan body myopathy 2)
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Robin H. Lachmann, Janice L. Holton, Ros Quinlivan, M. Desikan, Anthony H.V. Schapira, Renata S Scalco, Rahul Phadke, Andreea Manole, Henry Houlden, and A. Gardiner
- Subjects
0301 basic medicine ,Weakness ,Pathology ,medicine.medical_specialty ,Molecular resolution ,03 medical and health sciences ,0302 clinical medicine ,Muscular Diseases ,medicine ,Humans ,Glycogen storage disease ,LIMB GIRDLE MUSCLE WEAKNESS ,POLYGLUCOSAN BODY MYOPATHY 2 ,Muscle, Skeletal ,Myopathy ,Genetics (clinical) ,Glycoproteins ,Retrospective Studies ,Early onset ,Aged, 80 and over ,Muscle Weakness ,business.industry ,Limb-girdle myopathy ,Glycogen Storage Disease ,medicine.disease ,Muscular Atrophy ,030104 developmental biology ,Neurology ,Glucosyltransferases ,Mutation ,Pediatrics, Perinatology and Child Health ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
An 84-year-old lady with slowly progressive limb and axial muscle weakness with onset in her teens was referred for genetic investigations. Targeted next generation sequencing (NGS) revealed a homozygous mutation GYG1 in exon5:c.487delG:p.D163fs, confirming the diagnosis of Polyglucosan Body Myopathy 2 (PGBM2). Retrospective review of muscle pathology revealed a florid vacuolar myopathy with histochemical and ultrastructural features consistent with a polyglucosan storage myopathy. No cardiac symptoms were reported. Our case is consistent with the core phenotype of GYG1-related PGBM2 apart from an early onset of weakness without cardiac symptoms. The presence of α-amylase resistant PAS-positive material in skeletal muscle biopsy of patients with slowly progressive limb girdle muscle weakness should prompt the search for GYG1 mutations. This case highlights the combined role of muscle pathology and NGS in the molecular resolution of patients with undiagnosed neuromuscular conditions.
- Published
- 2018
35. The role of glucocerebrosidase in Parkinson disease pathogenesis
- Author
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Anthony H.V. Schapira and Matthew E. Gegg
- Subjects
0301 basic medicine ,Mitochondrion ,Biology ,Biochemistry ,Gene Expression Regulation, Enzymologic ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Lysosome ,medicine ,Animals ,Humans ,Molecular Biology ,Neuroinflammation ,Inflammation ,Autophagy ,Parkinson Disease ,Cell Biology ,Mitochondria ,Glucosylceramidase ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Mutation ,Unfolded protein response ,Glucocerebrosidase ,030217 neurology & neurosurgery - Abstract
GBA encodes the lysosomal enzyme glucocerebrosidase (GCase), an enzyme involved in sphingolipid metabolism. Mutations in the GBA gene are numerically the most important risk factor for developing Parkinson disease (PD) accounting for at least 5% of all PD cases. Furthermore, loss of GCase activity is found in sporadic PD brains. Lysosomal dysfunction is thought to play a principal role in PD pathogenesis and in particular its effect on the metabolism of α-synuclein. A hallmark of PD is the presence of intraneuronal protein inclusions called Lewy bodies, which are composed mainly of α-synuclein. Cellular and animal models of GCase deficiency result in lysosomal dysfunction, and in particular the autophagy lysosome pathway, resulting in the accumulation of α-synuclein. Some forms of mutant GCase unfold in the endoplasmic reticulum activating the unfolded protein response, which might also contribute to PD pathogenesis. It has also been suggested that accumulation of GCase substrates glucosylceramide/glucosylsphingosine may contribute to GBA-PD pathogenesis. Mitochondrial dysfunction and neuroinflammation are associated with GCase deficiency and have also been implicated in the aetiology of PD. This review discusses these points and highlights potential treatments that might be effective in treating GCase deficiency in PD.
- Published
- 2018
36. Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy
- Author
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Eduard Tolosa, Glenda M. Halliday, Connie Marras, Joseph Jankovic, John C. Rothwell, David G. Standaert, David J. Brooks, J. W. Langston, Mark Hallett, Hagai Bergman, Günther Deuschl, W. Poewe, A. J. Stoessl, Kenneth Marek, Caroline M. Tanner, Christine Klein, Anthony E. Lang, Paolo Calabresi, Mahlon R. DeLong, Dalton James Surmeier, Anthony H.V. Schapira, Jose A. Obeso, David J. Burn, Daniela Berg, Maria Stamelou, Erwan Bezard, Christopher G. Goetz, Stanley Fahn, Serge Przedborski, C. W. Olanow, Andres M. Lozano, V. Bonifati, Stéphane Lehéricy, Mayela Rodríguez-Violante, Ronald B. Postuma, G. W. Ross, Jeffrey H. Kordower, and Daniel Weintraub
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Neurology ,Parkinson's disease ,business.industry ,Disease progression ,Disease ,medicine.disease ,03 medical and health sciences ,Shaking palsy ,030104 developmental biology ,0302 clinical medicine ,medicine ,Neurology (clinical) ,business ,Psychiatry ,Neuroscience ,030217 neurology & neurosurgery - Abstract
This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.
- Published
- 2017
37. Glucocerebrosidase Mutations in Parkinson Disease
- Author
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Anthony H.V. Schapira, Grace C. O’Regan, Roberta Balestrino, and Ruth-Mary deSouza
- Subjects
0301 basic medicine ,Genetically modified mouse ,Parkinson's disease ,Disease ,Biology ,Bioinformatics ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Lysosome ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Alpha-synuclein ,Autophagy ,Neurodegeneration ,Parkinson Disease ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Mutation ,Glucosylceramidase ,Neurology (clinical) ,Glucocerebrosidase ,030217 neurology & neurosurgery - Abstract
Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD.
- Published
- 2017
38. Pathogenetic insights into young-onset Parkinson disease
- Author
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Anthony H.V. Schapira and Huw R. Morris
- Subjects
0301 basic medicine ,Parkinson's disease ,business.industry ,Dopaminergic ,food and beverages ,Disease ,Bioinformatics ,medicine.disease ,Biochemical phenotype ,Young onset Parkinson disease ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,Medicine ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
An understanding of the biochemical processes underlying Parkinson disease (PD) will be essential for the development of disease-modifying therapies. In a recent study, a novel biochemical phenotype of the disease was identified from analysis of inducible pluripotent stem cell-derived dopaminergic neurons from individuals with young-onset PD.
- Published
- 2020
39. The biochemical basis of interactions between Glucocerebrosidase and alpha-synuclein in GBA1 mutation carriers
- Author
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Marco Toffoli, Anthony H.V. Schapira, and Laura Smith
- Subjects
0301 basic medicine ,Alpha-synuclein ,Genetics ,Heterozygote ,Parkinson Disease ,Disease ,Biology ,Biochemistry ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Increased risk ,chemistry ,Mutation (genetic algorithm) ,Mutation ,alpha-Synuclein ,Glucosylceramidase ,Humans ,Genetic Predisposition to Disease ,Protein Structure, Quaternary ,Glucocerebrosidase ,Gene ,030217 neurology & neurosurgery - Abstract
The discovery of genes involved in familial as well as sporadic forms of Parkinson disease (PD) constitutes an important milestone in understanding this disorder's pathophysiology and potential treatment. Among these genes, GBA1 is one of the most common and well-studied, but it is still unclear how mutations in GBA1 translate into an increased risk for developing PD. In this review, we provide an overview of the biochemical and structural relationship between GBA1 and PD to help understand the recent advances in the development of PD therapies intended to target this pathway.
- Published
- 2019
40. Unexpected opposing biological effect of genetic risk factors for Parkinson’s disease
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Nan Li, Lisa Watson, Anthony H.V. Schapira, Ryan B. MacDonald, Deepak Ailani, Mark J Dunning, Astrid van Leens, Dirk Lefeber, Marcus Keatinge, Heather Mortiboys, Hai Bui, Oliver Bandmann, and Matthew E. Gegg
- Subjects
Genetics ,Mitochondrial respiratory chain ,Mechanism (biology) ,medicine ,Disease ,Biology ,Acid sphingomyelinase ,biology.organism_classification ,Zebrafish ,Glucocerebrosidase ,Intracellular ,Homeostasis ,medicine.drug - Abstract
The additive effect of genetic risk variants on overall disease risk is a plausible but frequently unproven hypothesis. To test this hypothesis, we assessed the biological effect of combined glucocerebrosidase (GCase) and acid sphingomyelinase (ASM) deficiency. Variants in both glucocerebrosidase1 (GBA1) and sphingomyelinase (SMPD1) are genetic risk factors for Parkinson’s disease. Unexpectedly, ASM deficiency resulted in normalized behaviour and prolonged survival in gba1−/−;smpd1−/− double-mutant zebrafish compared to gba1−/−. RNAseq-based pathway analysis confirmed a profound rescue of neuronal function and intracellular homeostasis. We identified complete reciprocal rescue of mitochondrial respiratory chain function and abolished lipid membrane oxidation in gba1−/−;smpd1−/− compared to gba1−/− or smpd1−/− as the underlying rescue mechanism. Complementing in vitro experiments demonstrated an unexpected reduction of α-synuclein levels in human cell lines with combined GCase and ASM deficiency. Our study highlights the importance of functional validation for any putative interactions between genetic risk factors and their overall effect on disease-relevant mechanisms rather than readily assuming an additive effect.SummaryThe additive effect of genetic risk variants on disease risk is a popular but typically unproven hypothesis. We investigated this hypothesis mechanistically for Parkinson’s disease risk factors and provide evidence of an unexpected rescue effect on neuronal function and survival.
- Published
- 2019
41. GBA mutation promotes early mitochondrial dysfunction in 3D neurosphere models
- Author
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Glòria Garrabou, Matthew E. Gegg, Constanza Morén, Francesc Cardellach, Diana Luz Juárez-Flores, Ingrid González-Casacuberta, Eduardo Tolosa, María José Martí, Kai-Yin Chau, Mariona Guitart-Mampel, and Anthony H.V. Schapira
- Subjects
autophagy ,Aging ,Parkinson's disease ,Mutant ,Mitochondrion ,Biology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Neurosphere ,Malaltia de Parkinson ,Gaucher's disease ,neurospheres ,medicine ,030304 developmental biology ,0303 health sciences ,Mutation ,Malaltia de Gaucher ,Autophagy ,Heterozygote advantage ,Cell Biology ,Cell biology ,mitochondria ,Stem cell ,Glucocerebrosidase ,030217 neurology & neurosurgery ,Research Paper - Abstract
Glucocerebrosidase (GBA) mutations are the most important genetic risk factor for the development of Parkinson disease (PD). GBA encodes the lysosomal enzyme glucocerebrosidase (GCase). Loss-of-GCase activity in cellular models has implicated lysosomal and mitochondrial dysfunction in PD disease pathogenesis, although the exact mechanisms remain unclear. We hypothesize that GBA mutations impair mitochondria quality control in a neurosphere model. We have characterized mitochondrial content, mitochondrial function and macroautophagy flux in 3D-neurosphere-model derived from neural crest stem cells containing heterozygous and homozygous N370SGBA mutations, under carbonyl cyanide-m-chlorophenyl-hydrazine (CCCP)- induced mitophagy. Our findings on mitochondrial markers and ATP levels indicate that mitochondrial accumulation occurs in mutant N370SGBA neurospheres under basal conditions, and clearance of depolarised mitochondria is impaired following CCCP-treatment. A significant increase in TFEB-mRNA levels, the master regulator of lysosomal and autophagy genes, may explain an unchanged macroautophagy flux in N370SGBA neurospheres. PGC1α-mRNA levels were also significantly increased following CCCP-treatment in heterozygote, but not homozygote neurospheres, and might contribute to the increased mitochondrial content seen in cells with this genotype, probably as a compensatory mechanism that is absent in homozygous lines. Mitochondrial impairment occurs early in the development of GCase-deficient neurons. Furthermore, impaired turnover of depolarised mitochondria is associated with early mitochondrial dysfunction. In summary, the presence of GBA mutation may be associated with higher levels of mitochondrial content in homozygous lines and lower clearance of damaged mitochondria in our neurosphere model.
- Published
- 2019
42. Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine
- Author
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Fabio Blandini, Anthony H.V. Schapira, José L. Lanciego, Gianni Pezzoli, Roberto Cilia, Stephen Mullin, and Silvia Cerri
- Subjects
0301 basic medicine ,Parkinson's disease ,Synucleinopathies ,Disease ,03 medical and health sciences ,Glucocerebrosidase activity ,0302 clinical medicine ,Medicine ,Humans ,Precision Medicine ,Gaucher Disease ,business.industry ,Dementia with Lewy bodies ,medicine.disease ,Precision medicine ,Phenotype ,030104 developmental biology ,Neurology ,alpha-Synuclein ,Glucosylceramidase ,Neurology (clinical) ,business ,Lysosomes ,Neuroscience ,Glucocerebrosidase ,030217 neurology & neurosurgery - Abstract
Glucocerebrosidase is a lysosomal enzyme. The characterization of a direct link between mutations in the gene coding for glucocerebrosidase (GBA1) with the development of Parkinson's disease and dementia with Lewy bodies has heightened interest in this enzyme. Although the mechanisms through which glucocerebrosidase regulates the homeostasis of α-synuclein remains poorly understood, the identification of reduced glucocerebrosidase activity in the brains of patients with PD and dementia with Lewy bodies has paved the way for the development of novel therapeutic strategies directed at enhancing glucocerebrosidase activity and reducing α-synuclein burden, thereby slowing down or even preventing neuronal death. Here we reviewed the current literature relating to the mechanisms underlying the cross talk between glucocerebrosidase and α-synuclein, the GBA1 mutation-associated clinical phenotypes, and ongoing therapeutic approaches targeting glucocerebrosidase. © 2018 International Parkinson and Movement Disorder Society.
- Published
- 2019
- Full Text
- View/download PDF
43. Molecular changes in the postmortem parkinsonian brain
- Author
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Anthony H.V. Schapira, Damien Toulorge, and Rodolphe Hajj
- Subjects
0301 basic medicine ,Mitochondrial Turnover ,Mitochondrion ,Gene mutation ,medicine.disease_cause ,Biochemistry ,Progressive supranuclear palsy ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Chaperone-mediated autophagy ,medicine ,Animals ,Humans ,Neurodegeneration ,Brain ,Parkinson Disease ,medicine.disease ,Mitochondria ,Oxidative Stress ,030104 developmental biology ,Autopsy ,Alzheimer's disease ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease. Although PD has a relatively narrow clinical phenotype, it has become clear that its etiological basis is broad. Post-mortem brain analysis, despite its limitations, has provided invaluable insights into relevant pathogenic pathways including mitochondrial dysfunction, oxidative stress and protein homeostasis dysregulation. Identification of the genetic causes of PD followed the discovery of these abnormalities, and reinforced the importance of the biochemical defects identified post-mortem. Recent genetic studies have highlighted the mitochondrial and lysosomal areas of cell function as particularly significant in mediating the neurodegeneration of PD. Thus the careful analysis of post-mortem PD brain biochemistry remains a crucial component of research, and one that offers considerable opportunity to pursue etiological factors either by 'reverse biochemistry' i.e. from defective pathway to mutant gene, or by the complex interplay between pathways e.g. mitochondrial turnover by lysosomes. In this review we have documented the spectrum of biochemical defects identified in PD post-mortem brain and explored their relevance to metabolic pathways involved in neurodegeneration. We have highlighted the complex interactions between these pathways and the gene mutations causing or increasing risk for PD. These pathways are becoming a focus for the development of disease modifying therapies for PD. Parkinson's is accompanied by multiple changes in the brain that are responsible for the progression of the disease. We describe here the molecular alterations occurring in postmortem brains and classify them as: Neurotransmitters and neurotrophic factors; Lewy bodies and Parkinson's-linked genes; Transition metals, calcium and calcium-binding proteins; Inflammation; Mitochondrial abnormalities and oxidative stress; Abnormal protein removal and degradation; Apoptosis and transduction pathways. This article is part of a special issue on Parkinson disease.
- Published
- 2016
44. Glucocerebrosidase in Parkinson's disease: Insights into pathogenesis and prospects for treatment
- Author
-
Tommaso Beccari, Davide Chiasserini, Lucilla Parnetti, and Anthony H.V. Schapira
- Subjects
0301 basic medicine ,Alpha-synuclein ,Parkinson's disease ,Neurodegeneration ,Biology ,medicine.disease ,Neuroprotection ,Pathogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Neurology ,chemistry ,Lysosome ,Cancer research ,medicine ,Substrate reduction therapy ,Neurology (clinical) ,Glucocerebrosidase ,Neuroscience ,030217 neurology & neurosurgery - Abstract
PD involves several converging pathogenetic pathways to neurodegeneration; highlighted in specific cases by genetic mutations causing familial PD. Numerically, the most important genetic mutations associated with PD are those of the glucocerebrosidase gene. Approximately 10% of PD patients carry glucocerebrosidase mutations. This observation has enhanced focus on the autophagy-lysosome system as important in pathogenesis. The relationship of the glucocerebrosidase pathway to the cause and progression of PD highlights the potential to use abnormalities identified as biomarkers and modify glucocerebrosidase activity or substrate accumulation as neuroprotection. Biomarkers relevant to the glucocerebrosidase pathway, for example, enzyme activity and substrate levels, may be identified in blood, urine, and CSF. These may be combined with clinical features to help identify mutation carriers that are at increased risk of PD. The molecular mechanisms by which glucocerebrosidase mutations may result in PD are not fully understood. There is evidence accumulating that there is a reciprocal interaction between glucocerebrosidase and alpha-synuclein levels. This interaction may potentially be used to increase glucocerebrosidase enzyme activities and therefore reduce alpha-synuclein levels to modify the course of PD. Substrate reduction therapy may be an alternative strategy, particularly if membrane abnormalities underlie the organellar dysfunction in PD neurodegeneration. © 2016 International Parkinson and Movement Disorder Society.
- Published
- 2016
45. PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy
- Author
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Kai-Yin Chau, Heather L. Smith, Kenneth Robert Pryde, and Anthony H.V. Schapira
- Subjects
0301 basic medicine ,Scaffold protein ,Ubiquitin-Protein Ligases ,Mitochondrial Degradation ,PINK1 ,Mitochondrion ,Biology ,Mitochondrial Dynamics ,Parkin ,Cell Line ,Substrate Specificity ,03 medical and health sciences ,Report ,Mitophagy ,Humans ,Gene Silencing ,Phosphorylation ,Protein kinase A ,Research Articles ,Genetics ,Cell Biology ,nervous system diseases ,Mitochondria ,Cell biology ,030104 developmental biology ,Calcium ,Mitochondrial fission ,Protein Kinases - Abstract
In addition to recruiting Parkin/autophagy receptors to damaged mitochondria, the authors show that PINK1 triggers PKA displacement from AKAP1 after damage to trigger mitochondrial fission in a Parkin-independent manner, suggesting that PINK1 is a master mitophagy regulator., Mitochondrial fission is essential for the degradation of damaged mitochondria. It is currently unknown how the dynamin-related protein 1 (DRP1)–associated fission machinery is selectively targeted to segregate damaged mitochondria. We show that PTEN-induced putative kinase (PINK1) serves as a pro-fission signal, independently of Parkin. Normally, the scaffold protein AKAP1 recruits protein kinase A (PKA) to the outer mitochondrial membrane to phospho-inhibit DRP1. We reveal that after damage, PINK1 triggers PKA displacement from A-kinase anchoring protein 1. By ejecting PKA, PINK1 ensures the requisite fission of damaged mitochondria for organelle degradation. We propose that PINK1 functions as a master mitophagy regulator by activating Parkin and DRP1 in response to damage. We confirm that PINK1 mutations causing Parkinson disease interfere with the orchestration of selective fission and mitophagy by PINK1.
- Published
- 2016
46. Mitochondrial and lysosomal biogenesis are activated following <scp>PINK</scp> 1/parkin‐mediated mitophagy
- Author
-
Davor Ivankovic, Matthew E. Gegg, Anthony H.V. Schapira, and Kai-Yin Chau
- Subjects
0301 basic medicine ,Carbonyl Cyanide m-Chlorophenyl Hydrazone ,Time Factors ,Ubiquitin-Protein Ligases ,Parkinson's disease ,Mitochondrial Degradation ,Receptors, Cell Surface ,PINK1 ,Biology ,Mitochondrion ,Transfection ,Biochemistry ,Nrf2 ,Parkin ,Neuroblastoma ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Cytosol ,lysosomes ,Tubulin ,Cell Line, Tumor ,Mitochondrial Precursor Protein Import Complex Proteins ,Sequestosome-1 Protein ,Mitophagy ,Humans ,RNA, Small Interfering ,Heat-Shock Proteins ,Molecular Basis of Disease ,TFEB ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Autophagy ,Membrane Transport Proteins ,Mitochondria ,Cell biology ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Gene Expression Regulation ,Mitochondrial biogenesis ,Proton Ionophores ,Original Article ,ORIGINAL ARTICLES ,Protein Kinases ,Cell Nucleolus - Abstract
Impairment of the autophagy–lysosome pathway is implicated with the changes in α‐synuclein and mitochondrial dysfunction observed in Parkinson's disease (PD). Damaged mitochondria accumulate PINK1, which then recruits parkin, resulting in ubiquitination of mitochondrial proteins. These can then be bound by the autophagic proteins p62/SQSTM1 and LC3, resulting in degradation of mitochondria by mitophagy. Mutations in PINK1 and parkin genes are a cause of familial PD. We found a significant increase in the expression of p62/SQSTM1 mRNA and protein following mitophagy induction in human neuroblastoma SH‐SY5Y cells. p62 protein not only accumulated on mitochondria, but was also greatly increased in the cytosol. Increased p62/SQSMT1 expression was prevented in PINK1 knock‐down cells, suggesting increased p62 expression was a consequence of mitophagy induction. The transcription factors Nrf2 and TFEB, which play roles in mitochondrial and lysosomal biogenesis, respectively, can regulate p62/SQSMT1. We report that both Nrf2 and TFEB translocate to the nucleus following mitophagy induction and that the increase in p62 mRNA levels was significantly impaired in cells with Nrf2 or TFEB knockdown. TFEB translocation also increased expression of itself and lysosomal proteins such as glucocerebrosidase and cathepsin D following mitophagy induction. We also report that cells with increased TFEB protein have significantly higher PGC‐1α mRNA levels, a regulator of mitochondrial biogenesis, resulting in increased mitochondrial content. Our data suggests that TFEB is activated following mitophagy to maintain autophagy–lysosome pathway and mitochondrial biogenesis. Therefore, strategies to increase TFEB may improve both the clearance of α‐synuclein and mitochondrial dysfunction in PD. Damaged mitochondria are degraded by the autophagy–lysosome pathway and is termed mitophagy. Following mitophagy induction, the transcription factors Nrf2 and TFEB translocate to the nucleus, inducing the transcription of genes encoding for autophagic proteins such as p62, as well as lysosomal and mitochondrial proteins. We propose that these events maintain autophagic flux, replenish lysosomes and replace mitochondria.
- Published
- 2015
47. Neurology in evolution 2014-2015
- Author
-
Anthony H.V. Schapira
- Subjects
Cognitive science ,medicine.medical_specialty ,Population based cohort ,Neurology ,business.industry ,medicine ,Neurology (clinical) ,business ,Acute ischemic stroke ,Neuroscience ,Clinical neurology - Published
- 2015
48. Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations
- Author
-
Kevin Mills, Patricia Limousin, Wendy E. Heywood, Laura Smith, Philip Woodgate, Josh Elflein, Jenny Hällqvist, Philip Campbell, Joanne Hosking, Anthony H.V. Schapira, Jason Hehir, Sarah Cable, Thomas Foltynie, Adam Streeter, Katherine Lee, Gayle D’Souza, Rajeshree Khengar, Vincenzo Libri, Henrik Zetterberg, Stephen Mullin, and Marco Toffoli
- Subjects
Male ,medicine.medical_specialty ,Neurology ,Ambroxol ,Gene mutation ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Aged ,medicine.diagnostic_test ,Lumbar puncture ,business.industry ,Parkinson Disease ,Middle Aged ,Respiratory pharmacology ,Clinical trial ,Treatment Outcome ,Clinical research ,Tolerability ,Mutation ,Glucosylceramidase ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Mutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases β-glucocerebrosidase (GCase) enzyme activity and reduces α-synuclein levels. These observations support a potential role for ambroxol therapy in modifying a relevant pathogenetic pathway in PD.To assess safety, tolerability, cerebrospinal fluid (CSF) penetration, and target engagement of ambroxol therapy with GCase in patients with PD with and without GBA1 mutations.An escalating dose of oral ambroxol to 1.26 g per day.This single-center open-label noncontrolled clinical trial was conducted between January 11, 2017, and April 25, 2018, at the Leonard Wolfson Experimental Neuroscience Centre, a dedicated clinical research facility and part of the University College London Queen Square Institute of Neurology in London, United Kingdom. Participants were recruited from established databases at the Royal Free London Hospital and National Hospital for Neurology and Neurosurgery in London. Twenty-four patients with moderate PD were evaluated for eligibility, and 23 entered the study. Of those, 18 patients completed the study; 1 patient was excluded (failed lumbar puncture), and 4 patients withdrew (predominantly lumbar puncture-related complications). All data analyses were performed from November 1 to December 14, 2018.Primary outcomes at 186 days were the detection of ambroxol in the CSF and a change in CSF GCase activity.Of the 18 participants (15 men [83.3%]; mean [SD] age, 60.2 [9.7] years) who completed the study, 17 (8 with GBA1 mutations and 9 without GBA1 mutations) were included in the primary analysis. Between days 0 and 186, a 156-ng/mL increase in the level of ambroxol in CSF (lower 95% confidence limit, 129 ng/mL; P .001) was observed. The CSF GCase activity decreased by 19% (0.059 nmol/mL per hour; 95% CI, -0.115 to -0.002; P = .04). The ambroxol therapy was well tolerated, with no serious adverse events. An increase of 50 pg/mL (13%) in the CSF α-synuclein concentration (95% CI, 14-87; P = .01) and an increase of 88 ng/mol (35%) in the CSF GCase protein levels (95% CI, 40-137; P = .002) were observed. Mean (SD) scores on part 3 of the Movement Disorders Society Unified Parkinson Disease Rating Scale decreased (ie, improved) by 6.8 (7.1) points (95% CI, -10.4 to -3.1; P = .001). These changes were observed in patients with and without GBA1 mutations.The study results suggest that ambroxol therapy was safe and well tolerated; CSF penetration and target engagement of ambroxol were achieved, and CSF α-synuclein levels were increased. Placebo-controlled clinical trials are needed to examine whether ambroxol therapy is associated with changes in the natural progression of PD.ClinicalTrials.gov identifier: NCT02941822; EudraCT identifier: 2015-002571-24.
- Published
- 2020
49. Progress in neurology 2017-2018
- Author
-
Anthony H.V. Schapira
- Subjects
03 medical and health sciences ,medicine.medical_specialty ,0302 clinical medicine ,Neurology ,business.industry ,Family medicine ,medicine ,MEDLINE ,030212 general & internal medicine ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Published
- 2018
50. Evolution and clustering of prodromal parkinsonian features in GBA1 carriers
- Author
-
Timothy M. Cox, Christos Proukakis, Jonathan P. Bestwick, Anthony H.V. Schapira, Michelle Beavan, Stephen Mullin, Henrik Zetterberg, Atul Mehta, Derralynn Hughes, and Alisdair McNeill
- Subjects
0301 basic medicine ,Adult ,Male ,cognition ,medicine.medical_specialty ,Heterozygote ,Movement disorders ,Genotype ,Parkinson's ,prodromal ,Prodromal Symptoms ,Gene mutation ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Parkinsonian Disorders ,Internal medicine ,medicine ,Cluster Analysis ,Humans ,Prospective Studies ,Depression (differential diagnoses) ,Research Articles ,Aged ,business.industry ,glucocerebrosidase ,Montreal Cognitive Assessment ,Cognition ,Odds ratio ,Middle Aged ,16. Peace & justice ,Confidence interval ,3. Good health ,030104 developmental biology ,Cross-Sectional Studies ,Neurology ,Gaucher ,Mutation ,depression ,Disease Progression ,Glucosylceramidase ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Glucocerebrosidase ,030217 neurology & neurosurgery ,Research Article ,olfaction - Abstract
Background Five to 25% of patients with PD carry glucocerebrosidase gene mutations, and 10% to 30% of glucocerebrosidase carriers will develop PD by age 80. Stratification of PD risk in glucocerebrosidase carriers provides an opportunity to target disease‐modifying therapies. Objective Cross‐sectional and longitudinal survey of prodromal PD signs among glucocerebrosidase carriers. Design Prospective assessment of 82 glucocerebrosidase mutation carriers and 35 controls over 4 to 5 years for prodromal clinical PD features. Results At all time points, olfactory (measured using University of Pennsylvania Smell Identification Test) and cognitive (Montreal Cognitive Assessment) function and the International Parkinson and Movement Disorder Society UPDRS parts II and III scores were significantly worse amongst glucocerebrosidase mutation carriers. Progression to microsmia (odds ratio: 8.5; 95% confidence interval: 2.6–28.2; P
- Published
- 2018
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