149 results on '"Double KL"'
Search Results
2. Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord.
- Author
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Trist, BG, Genoud, S, Roudeau, S, Rookyard, A, Abdeen, A, Cottam, V, Hare, DJ, White, M, Altvater, J, Fifita, JA, Hogan, A, Grima, N, Blair, IP, Kysenius, K, Crouch, PJ, Carmona, A, Rufin, Y, Claverol, S, Van Malderen, S, Falkenberg, G, Paterson, DJ, Smith, B, Troakes, C, Vance, C, Shaw, CE, Al-Sarraj, S, Cordwell, S, Halliday, G, Ortega, R, Double, KL, Trist, BG, Genoud, S, Roudeau, S, Rookyard, A, Abdeen, A, Cottam, V, Hare, DJ, White, M, Altvater, J, Fifita, JA, Hogan, A, Grima, N, Blair, IP, Kysenius, K, Crouch, PJ, Carmona, A, Rufin, Y, Claverol, S, Van Malderen, S, Falkenberg, G, Paterson, DJ, Smith, B, Troakes, C, Vance, C, Shaw, CE, Al-Sarraj, S, Cordwell, S, Halliday, G, Ortega, R, and Double, KL
- Abstract
Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro and in transgenic animal models of amyotrophic lateral sclerosis. Detailed examination of the protein in disease-affected tissues from amyotrophic lateral sclerosis patients, however, remains scarce. We used histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from amyotrophic lateral sclerosis cases and controls. Tissues were dissected into ventral and dorsal spinal cord grey matter to assess the specificity of alterations within regions of motor neuron degeneration. We provide evidence of the mislocalization and accumulation of structurally disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked and non-SOD1-linked familial amyotrophic lateral sclerosis cases, and sporadic amyotrophic lateral sclerosis cases, compared with control motor neurons. These changes were collectively associated with instability and mismetallation of enzymatically active SOD1 dimers, as well as alterations to SOD1 post-translational modifications and molecular chaperones governing SOD1 maturation. Atypical changes to SOD1 protein were largely restricted to regions of neurodegeneration in amyotrophic lateral sclerosis cases, and clearly differentiated all forms of amyotrophic lateral sclerosis from controls. Substantial heterogeneity in the presence of these changes was also observed between amyotrophic lateral sclerosis cases. Our data demonstrate that varying forms of SOD1 proteinopathy are a common feature of all forms of amyotrophic lateral sclerosis, and support the presence of one or more convergent biochemical pathways leading to SOD1 proteinopathy in amyotrophic lateral sclerosis. Most of these alterations are specific to regions of neurodegeneration, and may th
- Published
- 2022
3. Superoxide Dismutase 1 in Health and Disease: How a Frontline Antioxidant Becomes Neurotoxic
- Author
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Trist, BG, Hilton, JB, Hare, DJ, Crouch, PJ, and Double, KL
- Subjects
Superoxide Dismutase-1 ,nervous system ,Central Nervous System Diseases ,Superoxides ,animal diseases ,Organic Chemistry ,Enzyme Stability ,Biocatalysis ,nutritional and metabolic diseases ,Humans ,03 Chemical Sciences ,Antioxidants ,nervous system diseases - Abstract
Cu/Zn superoxide dismutase (SOD1) is a frontline antioxidant enzyme catalysing superoxide breakdown and is important for most forms of eukaryotic life. The evolution of aerobic respiration by mitochondria increased cellular production of superoxide, resulting in an increased reliance upon SOD1. Consistent with the importance of SOD1 for cellular health, many human diseases of the central nervous system involve perturbations in SOD1 biology. But far from providing a simple demonstration of how disease arises from SOD1 loss-of-function, attempts to elucidate pathways by which atypical SOD1 biology leads to neurodegeneration have revealed unexpectedly complex molecular characteristics delineating healthy, functional SOD1 protein from that which likely contributes to central nervous system disease. This review summarises current understanding of SOD1 biology from SOD1 genetics through to protein function and stability.
- Published
- 2021
4. Simultaneous structural and elemental nano-imaging of human brain tissue
- Author
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Genoud S, Jones MWM, Trist BG, Deng J, Chen S, Hare DJ, and Double KL
- Subjects
03 Chemical Sciences - Abstract
Structural and chemical characterisation of microfeatures in unadulterated Parkinson's disease brain tissue using synchrotron nanoscale XFM and ptychography.
- Published
- 2020
5. Superoxide Dismutase 1 in Health and Disease: How a Frontline Antioxidant Becomes Neurotoxic
- Author
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Trist, BG, Hilton, JB, Hare, DJ, Crouch, PJ, Double, KL, Trist, BG, Hilton, JB, Hare, DJ, Crouch, PJ, and Double, KL
- Abstract
Cu/Zn superoxide dismutase (SOD1) is a frontline antioxidant enzyme catalysing superoxide breakdown and is important for most forms of eukaryotic life. The evolution of aerobic respiration by mitochondria increased cellular production of superoxide, resulting in an increased reliance upon SOD1. Consistent with the importance of SOD1 for cellular health, many human diseases of the central nervous system involve perturbations in SOD1 biology. But far from providing a simple demonstration of how disease arises from SOD1 loss-of-function, attempts to elucidate pathways by which atypical SOD1 biology leads to neurodegeneration have revealed unexpectedly complex molecular characteristics delineating healthy, functional SOD1 protein from that which likely contributes to central nervous system disease. This review summarises current understanding of SOD1 biology from SOD1 genetics through to protein function and stability.
- Published
- 2020
6. Simultaneous structural and elemental nano-imaging of human brain tissue
- Author
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Genoud, S, Jones, MWM, Trist, BG, Deng, J, Chen, S, Hare, DJ, Double, KL, Genoud, S, Jones, MWM, Trist, BG, Deng, J, Chen, S, Hare, DJ, and Double, KL
- Abstract
Examining chemical and structural characteristics of micro-features in complex tissue matrices is essential for understanding biological systems. Advances in multimodal chemical and structural imaging using synchrotron radiation have overcome many issues in correlative imaging, enabling the characterization of distinct microfeatures at nanoscale resolution in ex vivo tissues. We present a nanoscale imaging method that pairs X-ray ptychography and X-ray fluorescence microscopy (XFM) to simultaneously examine structural features and quantify elemental content of microfeatures in complex ex vivo tissues. We examined the neuropathological microfeatures Lewy bodies, aggregations of superoxide dismutase 1 (SOD1) and neuromelanin in human post-mortem Parkinson's disease tissue. Although biometals play essential roles in normal neuronal biochemistry, their dyshomeostasis is implicated in Parkinson's disease aetiology. Here we show that Lewy bodies and SOD1 aggregates have distinct elemental fingerprints yet are similar in structure, whilst neuromelanin exhibits different elemental composition and a distinct, disordered structure. The unique approach we describe is applicable to the structural and chemical characterization of a wide range of complex biological tissues at previously unprecedented levels of detail.
- Published
- 2020
7. Meta-analysis of copper and iron in Parkinson's disease brain and biofluids.
- Author
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Genoud, S, Senior, AM, Hare, DJ, Double, KL, Genoud, S, Senior, AM, Hare, DJ, and Double, KL
- Abstract
BACKGROUND:Variations in study quality and design complicate interpretation of the clinical significance of consistently reported changes in copper and iron levels in human Parkinson's disease brain and biofluids. METHODS:We systematically searched literature databases for quantitative reports of biometal levels in the degenerating substantia nigra (SN), CSF, serum, and plasma in Parkinson's disease compared with healthy age-matched controls and assessed the quality of these publications. The primary outcomes of our analysis confirmed SN copper and iron levels are decreased and increased, respectively, in the Parkinson's disease brain. We applied a novel Quality Assessment Scale for Human Tissue to categorize the quality of individual studies and investigated the effects of study quality on our outcomes. We undertook a random-effects meta-analysis and meta-regression subgroup analysis. RESULTS:In the 18 eligible studies identified (211 Parkinson's disease, 215 control cases), SN copper levels were significantly lower (d, -2.00; 95% CI, -2.81 to -1.19; P < 0.001), and iron levels were significantly higher (d, 1.31; 95% CI, 0.38-2.24; P < 0.01) in Parkinson's disease. No changes were detected in CSF, serum, or plasma for any metals (29 studies; 2443 Parkinson's disease and 2183 control cases) except serum iron, which was lower in Parkinson's disease (14 studies; 1177 Parkinson's disease and 1447 control cases). CONCLUSIONS:Reductions in copper levels and elevations in iron were confirmed as characteristic of the degenerating SN of Parkinson's disease. Iron in serum was also changed, but in the opposite direction to that in the SN and to a lesser extent. © 2019 International Parkinson and Movement Disorder Society.
- Published
- 2020
8. Meta-analysis of copper and iron in Parkinson's disease brain and biofluids
- Author
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Genoud, S, Senior, AM, Hare, DJ, and Double, KL
- Subjects
Neurology & Neurosurgery ,1103 Clinical Sciences, 1106 Human Movement and Sports Sciences, 1109 Neurosciences - Abstract
BACKGROUND:Variations in study quality and design complicate interpretation of the clinical significance of consistently reported changes in copper and iron levels in human Parkinson's disease brain and biofluids. METHODS:We systematically searched literature databases for quantitative reports of biometal levels in the degenerating substantia nigra (SN), CSF, serum, and plasma in Parkinson's disease compared with healthy age-matched controls and assessed the quality of these publications. The primary outcomes of our analysis confirmed SN copper and iron levels are decreased and increased, respectively, in the Parkinson's disease brain. We applied a novel Quality Assessment Scale for Human Tissue to categorize the quality of individual studies and investigated the effects of study quality on our outcomes. We undertook a random-effects meta-analysis and meta-regression subgroup analysis. RESULTS:In the 18 eligible studies identified (211 Parkinson's disease, 215 control cases), SN copper levels were significantly lower (d, -2.00; 95% CI, -2.81 to -1.19; P
- Published
- 2019
9. Reduction in IGF1 mRNA in the human subependymal zone during aging
- Author
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Weissleder, C, Barry, G, Fung, SJ, Wong, MW, Double, KL, Webster, MJ, Weickert, CS, Weissleder, C, Barry, G, Fung, SJ, Wong, MW, Double, KL, Webster, MJ, and Weickert, CS
- Abstract
The cell proliferation marker, Ki67 and the immature neuron marker, doublecortin are both expressed in the major human neurogenic niche, the subependymal zone (SEZ), but expression progressively decreases across the adult lifespan (PMID: 27932973). In contrast, transcript levels of several mitogens (transforming growth factor α, epidermal growth factor and fibroblast growth factor 2) do not decline with age in the human SEZ, suggesting that other growth factors may contribute to the reduced neurogenic potential. While insulin like growth factor 1 (IGF1) regulates neurogenesis throughout aging in the mouse brain, the extent to which IGF1 and IGF family members change with age and relate to adult neurogenesis markers in the human SEZ has not yet been determined. We used quantitative polymerase chain reaction to examine gene expression of seven IGF family members [IGF1, IGF1 receptor, insulin receptor and high-affinity IGF binding proteins (IGFBPs) 2, 3, 4 and 5] in the human SEZ across the adult lifespan (n=50, 21-103 years). We found that only IGF1 expression significantly decreased with increasing age. IGFBP2 and IGFBP4 expression positively correlated with Ki67 mRNA. IGF1 expression positively correlated with doublecortin mRNA, whereas IGFBP2 expression negatively correlated with doublecortin mRNA. Our results suggest IGF family members are local regulators of neurogenesis and indicate that the age-related reduction in IGF1 mRNA may limit new neuron production by restricting neuronal differentiation in the human SEZ.
- Published
- 2019
10. Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease
- Author
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Trist, BG, Hare, DJ, Double, KL, Trist, BG, Hare, DJ, and Double, KL
- Abstract
Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease-modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady-state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.
- Published
- 2019
11. A Proposed Mechanism for Neurodegeneration in Movement Disorders Characterized by Metal Dyshomeostasis and Oxidative Stress
- Author
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Trist, BG, Hare, DJ, Double, KL, Trist, BG, Hare, DJ, and Double, KL
- Abstract
© 2018 Elsevier Ltd Shared molecular pathologies between distinct neurodegenerative disorders offer unique opportunities to identify common mechanisms of neuron death, and apply lessons learned from one disease to another. Neurotoxic superoxide dismutase 1 (SOD1) proteinopathy in SOD1-associated familial amyotrophic lateral sclerosis (fALS) is recapitulated in idiopathic Parkinson disease (PD), suggesting that these two phenotypically distinct disorders share an etiological pathway, and tractable therapeutic target(s). Despite 25 years of research, the molecular determinants underlying SOD1 misfolding and toxicity in fALS remain poorly understood. The absence of SOD1 mutations in PD highlights mounting evidence that SOD1 mutations are not the sole cause of SOD1 protein misfolding occasioning oligomerization and toxicity, reinforcing the importance of non-genetic factors, including protein metallation and post-translational modification in determining SOD1 stability and function. We propose that these non-genetic factors underlie the misfolding and dysfunction of SOD1 and other proteins in both PD and fALS, constituting a shared and tractable pathway to neurodegeneration. Trist et al. propose a shared etiological pathway in Parkinson disease and SOD1-associated familial amyotrophic lateral sclerosis, whereby concomitant changes in cellular copper and oxidative stress within dying neurons contribute to the dysfunction of specific proteins that are essential for maintaining neuronal health, including superoxide dismutase 1.
- Published
- 2018
12. Accumulation of dysfunctional SOD1 protein in Parkinson’s disease is not associated with mutations in the SOD1 gene
- Author
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Trist, BG, Fifita, JA, Freckleton, SE, Hare, DJ, Lewis, SJG, Halliday, GM, Blair, IP, Double, KL, Trist, BG, Fifita, JA, Freckleton, SE, Hare, DJ, Lewis, SJG, Halliday, GM, Blair, IP, and Double, KL
- Published
- 2018
13. Accumulation of dysfunctional SOD1 protein in Parkinson’s disease is not associated with mutations in the SOD1 gene
- Author
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Trist, BG, Fifita, JA, Freckleton, SE, Hare, DJ, Lewis, SJG, Halliday, GM, Blair, IP, and Double, KL
- Subjects
Cohort Studies ,Protein Aggregates ,Neurology & Neurosurgery ,Superoxide Dismutase-1 ,Mutation ,Humans ,Parkinson Disease - Published
- 2017
14. Subcellular compartmentalisation of copper, iron, manganese, and zinc in the Parkinson's disease brain
- Author
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Genoud, S, Roberts, BR, Gunn, AP, Halliday, GM, Lewis, SJG, Ball, HJ, Hare, DJ, and Double, KL
- Subjects
Adult ,Aged, 80 and over ,Male ,Manganese ,Iron ,Brain ,Parkinson Disease ,Middle Aged ,Analytical Chemistry ,Zinc ,nervous system ,Case-Control Studies ,Humans ,Female ,Copper ,Subcellular Fractions ,Aged - Abstract
© 2017 The Royal Society of Chemistry. Elevated iron and decreased copper levels are cardinal features of the degenerating substantia nigra pars compacta in the Parkinson's disease brain. Both of these redox-active metals, and fellow transition metals manganese and zinc, are found at high concentrations within the midbrain and participate in a range of unique biological reactions. We examined the total metal content and cellular compartmentalisation of manganese, iron, copper and zinc in the degenerating substantia nigra, disease-affected but non-degenerating fusiform gyrus, and unaffected occipital cortex in the post mortem Parkinson's disease brain compared with age-matched controls. An expected increase in iron and a decrease in copper concentration was isolated to the soluble cellular fraction, encompassing both interstitial and cytosolic metals and metal-binding proteins, rather than the membrane-associated or insoluble fractions. Manganese and zinc levels did not differ between experimental groups. Altered Fe and Cu levels were unrelated to Braak pathological staging in our cases of late-stage (Braak stage V and VI) disease. The data supports our hypothesis that regional alterations in Fe and Cu, and in proteins that utilise these metals, contribute to the regional selectively of neuronal vulnerability in this disorder.
- Published
- 2017
15. Evidence for reduced neurogenesis in the aging human hippocampus despite stable stem cell markers
- Author
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Mathews, KJ, Allen, KM, Boerrigter, D, Ball, H, Shannon Weickert, C, Double, KL, Mathews, KJ, Allen, KM, Boerrigter, D, Ball, H, Shannon Weickert, C, and Double, KL
- Abstract
Reduced neurogenesis in the aging mammalian hippocampus has been linked to cognitive deficits and increased risk of dementia. We utilized postmortem human hippocampal tissue from 26 subjects aged 18–88 years to investigate changes in expression of six genes representing different stages of neurogenesis across the healthy adult lifespan. Progressive and significant decreases in mRNA levels of the proliferation marker Ki67 (MKI67) and the immature neuronal marker doublecortin (DCX) were found in the healthy human hippocampus over the lifespan. In contrast, expression of genes for the stem cell marker glial fibrillary acidic protein delta and the neuronal progenitor marker eomesodermin was unchanged with age. These data are consistent with a persistence of the hippocampal stem cell population with age. Age-associated expression of the proliferation and immature neuron markers MKI67 and DCX, respectively, was unrelated, suggesting that neurogenesis-associated processes are independently altered at these points in the development from stem cell to neuron. These data are the first to demonstrate normal age-related decreases at specific stages of adult human hippocampal neurogenesis.
- Published
- 2017
16. Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain
- Author
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Purves-Tyson, TD, Owens, SJ, Rothmond, DA, Halliday, GM, Double, KL, Stevens, J, McCrossin, T, Shannon Weickert, C, Purves-Tyson, TD, Owens, SJ, Rothmond, DA, Halliday, GM, Double, KL, Stevens, J, McCrossin, T, and Shannon Weickert, C
- Abstract
The dopamine hypothesis of schizophrenia posits that increased subcortical dopamine underpins psychosis. In vivo imaging studies indicate an increased presynaptic dopamine synthesis capacity in striatal terminals and cell bodies in the midbrain in schizophrenia; however, measures of the dopamine-synthesising enzyme, tyrosine hydroxylase (TH), have not identified consistent changes. We hypothesise that dopamine dysregulation in schizophrenia could result from changes in expression of dopamine synthesis enzymes, receptors, transporters or catabolic enzymes. Gene expression of 12 dopamine-related molecules was examined in post-mortem midbrain (28 antipsychotic-treated schizophrenia cases/29 controls) using quantitative PCR. TH and the synaptic dopamine transporter (DAT) proteins were examined in post-mortem midbrain (26 antipsychotic-treated schizophrenia cases per 27 controls) using immunoblotting. TH and aromatic acid decarboxylase (AADC) mRNA and TH protein were unchanged in the midbrain in schizophrenia compared with controls. Dopamine receptor D2 short, vesicular monoamine transporter (VMAT2) and DAT mRNAs were significantly decreased in schizophrenia, with no change in DRD3 mRNA, DRD3nf mRNA and DAT protein between diagnostic groups. However, DAT protein was significantly increased in putatively treatment-resistant cases of schizophrenia compared to putatively treatment-responsive cases. Midbrain monoamine oxidase A (MAOA) mRNA was increased, whereas MAOB and catechol-O-methyl transferase mRNAs were unchanged in schizophrenia. We conclude that, whereas some mRNA changes are consistent with increased dopamine action (decreased DAT mRNA), others suggest reduced dopamine action (increased MAOA mRNA) in the midbrain in schizophrenia. Here, we identify a molecular signature of dopamine dysregulation in the midbrain in schizophrenia that mainly includes gene expression changes of molecules involved in dopamine synthesis and in regulating the time course of dopamine act
- Published
- 2017
17. Excessive early-life dietary exposure: a potential source of elevated brain iron and a risk factor for Parkinson's disease
- Author
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Hare, DJ, Cardoso, BR, Raven, EP, Double, KL, Finkelstein, DI, Szymlek-Gay, EA, Biggs, B-A, Hare, DJ, Cardoso, BR, Raven, EP, Double, KL, Finkelstein, DI, Szymlek-Gay, EA, and Biggs, B-A
- Abstract
Iron accumulates gradually in the ageing brain. In Parkinson's disease, iron deposition within the substantia nigra is further increased, contributing to a heightened pro-oxidant environment in dopaminergic neurons. We hypothesise that individuals in high-income countries, where cereals and infant formulae have historically been fortified with iron, experience increased early-life iron exposure that predisposes them to age-related iron accumulation in the brain. Combined with genetic factors that limit iron regulatory capacity and/or dopamine metabolism, this may increase the risk of Parkinson's diseases. We propose to (a) validate a retrospective biomarker of iron exposure in children; (b) translate this biomarker to adults; (c) integrate it with in vivo brain iron in Parkinson's disease; and (d) longitudinally examine the relationships between early-life iron exposure and metabolism, brain iron deposition and Parkinson's disease risk. This approach will provide empirical evidence to support therapeutically addressing brain iron deposition in Parkinson's diseases and produce a potential biomarker of Parkinson's disease risk in preclinical individuals.
- Published
- 2017
18. Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated with neuronal loss in Parkinson’s disease brain
- Author
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Trist, BG, Davies, KM, Cottam, V, Genoud, S, Ortega, R, Roudeau, S, Carmona, A, De Silva, K, Wasinger, V, Lewis, SJG, Sachdev, P, Smith, B, Troakes, C, Vance, C, Shaw, C, Al-Sarraj, S, Ball, HJ, Halliday, GM, Hare, DJ, Double, KL, Trist, BG, Davies, KM, Cottam, V, Genoud, S, Ortega, R, Roudeau, S, Carmona, A, De Silva, K, Wasinger, V, Lewis, SJG, Sachdev, P, Smith, B, Troakes, C, Vance, C, Shaw, C, Al-Sarraj, S, Ball, HJ, Halliday, GM, Hare, DJ, and Double, KL
- Abstract
© 2017, Springer-Verlag Berlin Heidelberg. Neuronal loss in numerous neurodegenerative disorders has been linked to protein aggregation and oxidative stress. Emerging data regarding overlapping proteinopathy in traditionally distinct neurodegenerative diseases suggest that disease-modifying treatments targeting these pathological features may exhibit efficacy across multiple disorders. Here, we describe proteinopathy distinct from classic synucleinopathy, predominantly comprised of the anti-oxidant enzyme superoxide dismutase-1 (SOD1), in the Parkinson’s disease brain. Significant expression of this pathology closely reflected the regional pattern of neuronal loss. The protein composition and non-amyloid macrostructure of these novel aggregates closely resembles that of neurotoxic SOD1 deposits in SOD1-associated familial amyotrophic lateral sclerosis (fALS). Consistent with the hypothesis that deposition of protein aggregates in neurodegenerative disorders reflects upstream dysfunction, we demonstrated that SOD1 in the Parkinson’s disease brain exhibits evidence of misfolding and metal deficiency, similar to that seen in mutant SOD1 in fALS. Our data suggest common mechanisms of toxic SOD1 aggregation in both disorders and a potential role for SOD1 dysfunction in neuronal loss in the Parkinson’s disease brain. This shared restricted proteinopathy highlights the potential translation of therapeutic approaches targeting SOD1 toxicity, already in clinical trials for ALS, into disease-modifying treatments for Parkinson’s disease.
- Published
- 2017
19. Iron and dopamine: A toxic couple
- Author
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Hare, DJ and Double, KL
- Subjects
Substantia Nigra ,Neurology & Neurosurgery ,Iron ,Dopamine ,Animals ,Humans ,Parkinson Disease ,Reactive Oxygen Species - Abstract
© 2016 The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. Iron accumulation is a cardinal feature of degenerating regions in the Parkinson's disease brain. As a potent pro-oxidant, redox-active iron may be a key player in upstream mechanisms that precipitate cell death in this disorder. Although an elevation in brain iron levels is a normal feature of ageing, the increase is greater in Parkinson's disease; on the other hand, the effects of the disease are most marked in the nigrostriatal dopaminergic system. In this Update, we explain that neurodegeneration in the affected regions may result from the potent redox couple formed by iron and dopamine itself, and discuss the clinical implications of this molecular trait in this dynamic and rapidly moving area of Parkinson's disease research.
- Published
- 2016
20. Comparative Study of Metal Quantification in Neurological Tissue Using Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry Imaging and X-ray Fluorescence Microscopy
- Author
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Davies, KM, Hare, DJ, Bohic, S, James, SA, Billings, JL, Finkelstein, DI, Doble, PA, and Double, KL
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Mice, Inbred C57BL ,Mice ,Microscopy, Fluorescence ,Metals ,Lasers ,Animals ,Nervous System ,Mass Spectrometry ,Analytical Chemistry - Abstract
© 2015 American Chemical Society. Redox-active metals in the brain mediate numerous biochemical processes and are also implicated in a number of neurodegenerative diseases. A number of different approaches are available for quantitatively measuring the spatial distribution of biometals at an image resolution approaching the subcellular level. Measured biometal levels obtained using laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS; spatial resolution 15 μm × 15 μm) were within the range of those obtained using X-ray fluorescence microscopy (XFM; spatial resolution 2 μm × 7 μm) and regional changes in metal concentration across discrete brain regions were replicated to the same degree. Both techniques are well suited to profiling changes in regional biometal distribution between healthy and diseased brain tissues, but absolute quantitation of metal levels varied significantly between methods, depending on the metal of interest. Where all possible variables affect metal levels, independent of a treatment/phenotype are controlled, either method is suitable for examining differences between experimental groups, though, as with any method for imaging post mortem brain tissue, care should be taken when interpreting the total metal levels with regard to physiological concentrations. (Figure Presented).
- Published
- 2015
21. Decline in proliferation and immature neuron markers in the human subependymal zone during aging: Relationship to EGF- and FGF-related transcripts
- Author
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Weissleder, C, Fung, SJ, Wong, MW, Barry, G, Double, KL, Halliday, GM, Webster, MJ, Weickert, CS, Weissleder, C, Fung, SJ, Wong, MW, Barry, G, Double, KL, Halliday, GM, Webster, MJ, and Weickert, CS
- Abstract
Neuroblasts exist within the human subependymal zone (SEZ); however, it is debated to what extent neurogenesis changes during normal aging. It is also unknown how precursor proliferation may correlate with the generation of neuronal and glial cells or how expression of growth factors and receptors may change throughout the adult lifespan. We found evidence of dividing cells in the human SEZ (n = 50) in conjunction with a dramatic age-related decline (21-103 years) of mRNAs indicative of proliferating cells (Ki67) and immature neurons (doublecortin). Microglia mRNA (ionized calcium-binding adapter molecule 1) increased during aging, whereas transcript levels of stem/precursor cells (glial fibrillary acidic protein delta and achaete-scute homolog 1), astrocytes (vimentin and pan-glial fibrillary acidic protein), and oligodendrocytes (oligodendrocyte lineage transcription factor 2) remained stable. Epidermal growth factor receptor (EGFR) and fibroblast growth factor 2 (FGF2) mRNAs increased throughout adulthood, while transforming growth factor alpha (TGFα), EGF, Erb-B2 receptor tyrosine kinase 4 (ErbB4) and FGF receptor 1 (FGFR1) mRNAs were unchanged across adulthood. Cell proliferation mRNA positively correlated with FGFR1 transcripts. Immature neuron and oligodendrocyte marker expression positively correlated with TGFα and ErbB4 mRNAs, whilst astrocyte transcripts positively correlated with EGF, FGF2, and FGFR1 mRNAs. Microglia mRNA positively correlated with EGF and FGF2 expression. Our findings indicate that neurogenesis in the human SEZ continues well into adulthood, although proliferation and neuronal differentiation may decline across adulthood. We suggest that mRNA expression of EGF- and FGF-related family members do not become limited during aging and may modulate neuronal and glial fate determination in the SEZ throughout human life.
- Published
- 2016
22. L-DOPA is incorporated into brain proteins of patients treated for Parkinson's disease, inducing toxicity in human neuroblastoma cells in vitro
- Author
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Chan, SW, Dunlop, RA, Rowe, A, Double, KL, and Rodgers, KJ
- Subjects
Brain Chemistry ,Neurology & Neurosurgery ,L-Lactate Dehydrogenase ,Cell Survival ,Hydrolysis ,Neurotoxins ,Parkinson Disease ,Nerve Tissue Proteins ,Apoptosis ,DNA Fragmentation ,Blood Protein Electrophoresis ,nervous system diseases ,Levodopa ,Antiparkinson Agents ,Microscopy, Electron ,Microscopy, Fluorescence ,Cell Line, Tumor ,Caspases ,Mitochondrial Membranes ,Quinolines ,Humans ,Indicators and Reagents ,Oxidation-Reduction ,Chromatography, High Pressure Liquid - Abstract
Levodopa (l-dopa), a close structural analogue of the protein amino acid l-tyrosine, can substitute for l-tyrosine in protein synthesis and be mistakenly incorporated into newly synthesised proteins in vitro. We show that l- dopa-containing proteins are present in the brain in l-DOPA-treated Parkinson's disease patients and accumulate in specific brain regions. In vitro studies demonstrate that substitution of l-tyrosine residues in proteins with l-DOPA causes protein misfolding and promotes protein aggregation in SH-SY5Y neuroblastoma cells resulting in the appearance of autofluorescent bodies. We show that the presence of l-DOPA-containing proteins causes profound changes in mitochondria and stimulates the formation of autophagic vacuoles in cells. Unlike l-DOPA, which is toxic to cells through its ability to generate radicals, proteins containing incorporated l-DOPA are toxic to SH-SY5Y cells by a mechanism independent of oxidative stress and resistant to antioxidants. These data suggest that the accumulation of l-DOPA-containing proteins in vulnerable cells might negatively impact on cell function. © 2011 Elsevier Inc.
- Published
- 2011
23. Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway
- Author
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Purves-Tyson, TD, Owens, SJ, Double, KL, Desai, R, Handelsman, DJ, Weickert, CS, Purves-Tyson, TD, Owens, SJ, Double, KL, Desai, R, Handelsman, DJ, and Weickert, CS
- Abstract
Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s) by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase), breakdown (catechol-O-methyl transferase; monoamine oxygenase), transport [vesicular monoamine transporter (VMAT), dopamine transporter (DAT)] and receptors (DRD1-D5)] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen receptor-driven event
- Published
- 2014
24. Hand function is impaired in healthy older adults at risk of Parkinson’s disease
- Author
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Todd, G, Haberfield, M, Faulkner, PL, Rae, C, Hayes, M, Wilcox, RA, Taylor, JL, Gandevia, SC, Godau, J, Berg, D, Piguet, O, Double, KL, Todd, G, Haberfield, M, Faulkner, PL, Rae, C, Hayes, M, Wilcox, RA, Taylor, JL, Gandevia, SC, Godau, J, Berg, D, Piguet, O, and Double, KL
- Abstract
Abnormal substantia nigra morphology in healthy individuals, viewed with transcranial ultrasound, is a significant risk factor for Parkinson’s disease. However, little is known about the functional consequences of this abnormality (termed ‘hyperechogenicity’) on movement. The aim of the current study was to investigate hand function in healthy older adults with (SN+) and without (SN-) substantia nigra hyperechogenicity during object manipulation. We hypothesised that SN+ subjects would exhibit increased grip force and a slower rate of force application compared to SN- subjects. Twenty-six healthy older adults (8 SN+ aged 58 ± 8 years, 18 SN- aged 57 ± 6 years) were asked to grip and lift a light-weight object with the dominant hand. Horizontal grip force, vertical lift force, acceleration, and first dorsal interosseus EMG were recorded during three trials. During the first trial, SN+ subjects exhibited a longer period between grip onset and lift onset (i.e. preload duration; 0.27 ± 0.25 s) than SN- subjects (0.13 ± 0.08 s; P = 0.046). They also exerted a greater downward force prior to lift off (-0.54 ± 0.42 N vs. -0.21 ± 0.12 N; P = 0.005) and used a greater grip force to lift the object (19.5 ± 7.0 N vs. 14.0 ± 4.3 N; P = 0.022) than SN-subjects. No between group differences were observed in subsequent trials. SN+ subjects exhibit impaired planning for manipulation of new objects. SN+ individuals overestimate the grip force required, despite a longer contact period prior to lifting the object. The pattern of impairment observed in SN+ subjects shares similarities with de novo Parkinson’s disease patients.
- Published
- 2014
25. Endogenous progesterone levels and frontotemporal dementia: Modulation of TDP-43 and Tau levels in vitro and treatment of the A315T TARDBP mouse model
- Author
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Dang, TNT, Dobson-Stone, C, Glaros, EN, Kim, WS, Hallupp, M, Bartley, L, Piguet, O, Hodges, JR, Halliday, GM, Double, KL, Schofield, PR, Crouch, PJ, Kwok, JBJ, Dang, TNT, Dobson-Stone, C, Glaros, EN, Kim, WS, Hallupp, M, Bartley, L, Piguet, O, Hodges, JR, Halliday, GM, Double, KL, Schofield, PR, Crouch, PJ, and Kwok, JBJ
- Abstract
Frontotemporal dementia (FTD) is associated with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Together, this group of disorders constitutes a major cause of young-onset dementia. One of the three clinical variants of FTD is progressive nonfluent aphasia (PNFA), which is focused on in this study. The steroid hormone progesterone (PROG) is known to have an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum samples (39 FTD, 91 controls), low serum PROG was associated with FTD overall. In subgroup analysis, low PROG levels were significantly associated with FTD-MND and CBS, but not with PSPS or PNFA. PROG levels of >195 pg/ml were significantly correlated with lower disease severity (frontotemporal dementia rating scale) for individuals with CBS. In the human neuroblastoma SK-N-MC cell line, exogenous PROG (9300-93,000 pg/ml) had a significant effect on overall Tau and nuclear TDP-43 levels, reducing total Tau levels by ~1.5-fold and increasing nuclear TDP-43 by 1.7- to 2.0-fold. Finally, elevation of plasma PROG to a mean concentration of 5870 pg/ml in an Ala315Thr (A315T) TARDBP transgenic mouse model significantly reduced the rate of loss of locomotor control in PROG-treated, compared with placebo, mice. The PROG treatment did not significantly increase survival of the mice, which might be due to the limitation of the transgenic mouse to accurately model TDP-43-mediated neurodegeneration. Together, our clinical, cellular and animal data provide strong evidence that PROG could be a valid therapy for specific related disorders of FTD.
- Published
- 2013
26. Trophic factors differentiate dopamine neurons vulnerable to Parkinson's disease
- Author
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Reyes, S, Fu, Y, Double, KL, Cottam, V, Thompson, LH, Kirik, D, Paxinos, G, Watson, C, Cooper, HM, Halliday, GM, Reyes, S, Fu, Y, Double, KL, Cottam, V, Thompson, LH, Kirik, D, Paxinos, G, Watson, C, Cooper, HM, and Halliday, GM
- Abstract
Recent studies suggest a variety of factors characterize substantia nigra neurons vulnerable to Parkinson's disease, including the transcription factors pituitary homeobox 3 (Pitx3) and orthodenticle homeobox 2 (Otx2) and the trophic factor receptor deleted in colorectal cancer (DCC), but there is limited information on their expression and localization in adult humans. Pitx3, Otx2, and DCC were immunohistochemically localized in the upper brainstem of adult humans and mice and protein expression assessed using relative intensity measures and online microarray data. Pitx3 was present and highly expressed in most dopamine neurons. Surprisingly, in our elderly subjects no Otx2 immunoreactivity was detected in dopamine neurons, although Otx2 gene expression was found in younger cases. Enhanced DCC gene expression occurred in the substantia nigra, and higher amounts of DCC protein characterized vulnerable ventral nigral dopamine neurons. Our data show that, at the age when Parkinson's disease typically occurs, there are no significant differences in the expression of transcription factors in brainstem dopamine neurons, but those most vulnerable to Parkinson's disease rely more on the trophic factor receptor DCC than other brainstem dopamine neurons.
- Published
- 2013
27. Localization of copper and copper transporters in the human brain
- Author
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Davies, KM, Hare, DJ, Cottam, V, Chen, N, Hilgers, L, Halliday, G, Mercer, JFB, Double, KL, Davies, KM, Hare, DJ, Cottam, V, Chen, N, Hilgers, L, Halliday, G, Mercer, JFB, and Double, KL
- Abstract
Disturbances in brain copper result in rare and severe neurological disorders and may play a role in the pathogenesis and progression of multiple neurodegenerative diseases. Our current understanding of mammalian brain copper transport is based on model systems outside the central nervous system and no data are available regarding copper transport systems in the human brain. To address this deficit, we quantified regional copper concentrations and examined the distribution and cellular localization of the copper transport proteins Copper transporter 1, Atox1, ATP7A, and ATP7B in multiple regions of the human brain using inductively coupled plasma-mass spectrometry, Western blot and immunohistochemistry. We identified significant relationships between copper transporter levels and brain copper concentrations, supporting a role for these proteins in copper transport in the human brain. Interestingly, the substantia nigra contained twice as much copper than that in other brain regions, suggesting an important role for copper in this brain region. Furthermore, ATP7A levels were significantly greater in the cerebellum, compared with other brain regions, supporting an important role for ATP7A in cerebellar neuronal health. This study provides novel data regarding copper regulation in the human brain, critical to understand the mechanisms by which brain copper levels can be altered, leading to neurological disease. © 2013 The Royal Society of Chemistry.
- Published
- 2013
28. Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra
- Author
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Purves-Tyson, TD, Handelsman, D, Double, KL, Bustamante, S, owens, SJ, Shannon Weickert, C, Purves-Tyson, TD, Handelsman, D, Double, KL, Bustamante, S, owens, SJ, and Shannon Weickert, C
- Abstract
Increased risk of schizophrenia in adolescent males indicates that a link between the development of dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found and most studies address this in adult animals. Testosterone-dependent actions in neurons are direct via activation of androgen receptors (AR) or indirect by conversion to 17â-estradiol and activation of estrogen receptors (ER). How midbrain dopamine neurons respond to sex steroids depends on the presence of sex steroid receptor(s) and the level of steroid conversion enzymes (aromatase and 5á-reductase). We investigated whether gonadectomy and sex steroid replacement could influence dopamine levels by changing tyrosine hydroxylase (TH) protein and mRNA and/or dopamine breakdown enzyme mRNA levels [catechol-O-methyl transferase (COMT) and monoamine oxygenase (MAO) A and B] in the adolescent male rat substantia nigra. We hypothesized that adolescent testosterone would regulate sex steroid signaling through regulation of ER and AR mRNAs and through modulation of aromatase and 5á-reductase mRNA levels.
- Published
- 2012
29. L-DOPA is incorporated into brain proteins of patients treated for Parkinson's disease, inducing toxicity in human neuroblastoma cells in vitro
- Author
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Chan, SW, Dunlop, RA, Rowe, A, Double, KL, Rodgers, KJ, Chan, SW, Dunlop, RA, Rowe, A, Double, KL, and Rodgers, KJ
- Abstract
Levodopa (l-dopa), a close structural analogue of the protein amino acid l-tyrosine, can substitute for l-tyrosine in protein synthesis and be mistakenly incorporated into newly synthesised proteins in vitro. We show that l- dopa-containing proteins are present in the brain in l-DOPA-treated Parkinson's disease patients and accumulate in specific brain regions. In vitro studies demonstrate that substitution of l-tyrosine residues in proteins with l-DOPA causes protein misfolding and promotes protein aggregation in SH-SY5Y neuroblastoma cells resulting in the appearance of autofluorescent bodies. We show that the presence of l-DOPA-containing proteins causes profound changes in mitochondria and stimulates the formation of autophagic vacuoles in cells. Unlike l-DOPA, which is toxic to cells through its ability to generate radicals, proteins containing incorporated l-DOPA are toxic to SH-SY5Y cells by a mechanism independent of oxidative stress and resistant to antioxidants. These data suggest that the accumulation of l-DOPA-containing proteins in vulnerable cells might negatively impact on cell function. © 2011 Elsevier Inc.
- Published
- 2012
30. Low serum progranulin predicts the presence of mutations: a prospective study.
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Schofield EC, Halliday GM, Kwok J, Loy C, Double KL, and Hodges JR
- Published
- 2010
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31. The background and experience of neuroscience teachers in Australian universities: A cross-sectional survey.
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Todd G, Kreilaus F, Lonergan AS, Cameron MS, and Double KL
- Subjects
- Humans, Australia, Universities, Male, Female, Cross-Sectional Studies, Surveys and Questionnaires, Teaching, Adult, Neurosciences education, Faculty
- Abstract
Neuroscience is an academic discipline taught within a broad range of university degrees and programs. The expertise and experience of neuroscience teaching staff contribute to the student's learning experience and knowledge acquisition. We undertook a survey to characterize the neuroscience teaching workforce and practices in Australian universities, and to investigate access to and deficiencies in neuroscience teaching resources and training. Two hundred neuroscience teaching staff completed our anonymous online survey. The responses indicated that neuroscience is primarily being delivered by highly qualified (86% with doctoral degrees, 27% with formal qualifications in tertiary teaching), research-active (45% were recently primary supervisors of research students) teaching academics with secure employment (77% in full-time continuing positions). There were more females (61.5%) than males (38.5%) in the sample and most respondents taught neuroscience to students enrolled in a range of degrees/programs. Most survey respondents could access an anatomy laboratory for teaching (87%) but access to specialised online resources, such as augmented reality presentations, customised game-based learning approaches, and/or online brain atlases, was limited. Most survey respondents reported they would benefit from increased access to neuroscience teaching resources and/or peer-tested teaching materials (80%), an informal network of Australian neuroscience teaching peers (64%), and/or training workshops on neuroscience teaching (59%). Approximately half of survey respondents supported the creation of national guidelines for neuroscience teaching curricula. The survey results identify specific gaps in teacher training and resources and inform the development of strategies to support tertiary teachers of neuroscience and student learning., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Todd et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2024
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32. Near-Infrared Ratiometric Fluorescent Probe for Detecting Endogenous Cu 2+ in the Brain.
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Zhu J, Graziotto ME, Cottam V, Hawtrey T, Adair LD, Trist BG, Pham NTH, Rouaen JRC, Ohno C, Heisler M, Vittorio O, Double KL, and New EJ
- Subjects
- Humans, Cell Line, Tumor, Lewy Body Disease diagnostic imaging, Lewy Body Disease metabolism, Optical Imaging methods, Fluorescent Dyes chemistry, Copper analysis, Brain diagnostic imaging, Brain metabolism
- Abstract
Copper participates in a range of critical functions in the nervous system and human brain. Disturbances in brain copper content is strongly associated with neurological diseases. For example, changes in the level and distribution of copper are reported in neuroblastoma, Alzheimer's disease, and Lewy body disorders, such as Parkinson disease and dementia with Lewy bodies (DLB). There is a need for more sensitive techniques to measure intracellular copper levels to have a better understanding of the role of copper homeostasis in neuronal disorders. Here, we report a reaction-based near-infrared (NIR) ratiometric fluorescent probe CyCu1 for imaging Cu
2+ in biological samples. High stability and selectivity of CyCu1 enabled the probe to be deployed as a sensor in a range of systems, including SH-SY5Y cells and neuroblastoma tumors. Furthermore, it can be used in plant cells, reporting on copper added to Arabidopsis roots. We also used CyCu1 to explore Cu2+ levels and distribution in post-mortem brain tissues from patients with DLB. We found significant decreases in Cu2+ content in the cytoplasm, neurons, and extraneuronal space in the degenerating substantia nigra in DLB compared with healthy age-matched control tissues. These findings enhance our understanding of Cu2+ dysregulation in Lewy body disorders. Our probe also shows promise as a photoacoustic imaging agent, with potential for applications in bimodal imaging.- Published
- 2024
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33. Empirically derived formulae for calculation of age- and region-related levels of iron, copper and zinc in the adult C57BL/6 mouse brain.
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Suryana E, Rowlands BD, Bishop DP, Finkelstein DI, and Double KL
- Subjects
- Mice, Animals, Iron metabolism, Mice, Inbred C57BL, Brain metabolism, Copper, Zinc metabolism
- Abstract
Metal dyshomeostasis is associated with neurodegenerative disorders, cancers and vascular disease. We report the effects of age (range: 3 to 18 months) on regional copper, iron and zinc levels in the brain of the C57BL/6 mouse, a widely used inbred strain with a permissive background allowing maximal expression of mutations in models that recapitulate these disorders. We present formulae that can be used to determine regional brain metal concentrations in the C57BL/6 mouse at any age in the range of three to eighteen months of life. Copper levels in the C57BL/6 mouse adult brain were highest in the striatum and cerebellum and increased with age, excepting the cortex and hippocampus. Regional iron levels increased linearly with age in all brain regions, while regional zinc concentrations became more homogeneous with age. Knockdown of the copper transporter Ctr1 reduced brain copper, but not iron or zinc, concentrations in a regionally-dependent manner. These findings demonstrate biometals in the brain change with age in a regionally-dependent manner. These data and associated formulae have implications for improving design and interpretation of a wide variety of studies in the C57BL/6 mouse., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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34. Responsible research practices could be more strongly endorsed by Australian university codes of research conduct.
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Ong YK, Double KL, Bero L, and Diong J
- Abstract
Background: This study aimed to investigate how strongly Australian university codes of research conduct endorse responsible research practices., Methods: Codes of research conduct from 25 Australian universities active in health and medical research were obtained from public websites, and audited against 19 questions to assess how strongly they (1) defined research integrity, research quality, and research misconduct, (2) required research to be approved by an appropriate ethics committee, (3) endorsed 9 responsible research practices, and (4) discouraged 5 questionable research practices., Results: Overall, a median of 10 (IQR 9 to 12) of 19 practices covered in the questions were mentioned, weakly endorsed, or strongly endorsed. Five to 8 of 9 responsible research practices were mentioned, weakly, or strongly endorsed, and 3 questionable research practices were discouraged. Results are stratified by Group of Eight (n = 8) and other (n = 17) universities. Specifically, (1) 6 (75%) Group of Eight and 11 (65%) other codes of research conduct defined research integrity, 4 (50%) and 8 (47%) defined research quality, and 7 (88%) and 16 (94%) defined research misconduct. (2) All codes required ethics approval for human and animal research. (3) All codes required conflicts of interest to be declared, but there was variability in how strongly other research practices were endorsed. The most commonly endorsed practices were ensuring researcher training in research integrity [8 (100%) and 16 (94%)] and making study data publicly available [6 (75%) and 12 (71%)]. The least commonly endorsed practices were making analysis code publicly available [0 (0%) and 0 (0%)] and registering analysis protocols [0 (0%) and 1 (6%)]. (4) Most codes discouraged fabricating data [5 (63%) and 15 (88%)], selectively deleting or modifying data [5 (63%) and 15 (88%)], and selective reporting of results [3 (38%) and 15 (88%)]. No codes discouraged p-hacking or hypothesising after results are known., Conclusions: Responsible research practices could be more strongly endorsed by Australian university codes of research conduct. Our findings may not be generalisable to smaller universities, or those not active in health and medical research., (© 2023. The Author(s).)
- Published
- 2023
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35. A Century of Progress on Wilson Disease and the Enduring Challenges of Genetics, Diagnosis, and Treatment.
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Penning LC, Berenguer M, Czlonkowska A, Double KL, Dusek P, Espinós C, Lutsenko S, Medici V, Papenthin W, Stremmel W, Willemse J, and Weiskirchen R
- Abstract
Wilson disease (WD) is a rare, inherited metabolic disorder manifested with varying clinical presentations including hepatic, neurological, psychiatric, and ophthalmological features, often in combination. Causative mutations in the ATP7B gene result in copper accumulation in hepatocytes and/or neurons, but clinical diagnosis remains challenging. Diagnosis is complicated by mild, non-specific presentations, mutations exerting no clear effect on protein function, and inconclusive laboratory tests, particularly regarding serum ceruloplasmin levels. As early diagnosis and effective treatment are crucial to prevent progressive damage, we report here on the establishment of a global collaboration of researchers, clinicians, and patient advocacy groups to identify and address the outstanding challenges posed by WD.
- Published
- 2023
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36. Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.
- Author
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Todd G, Rae CD, Taylor JL, Rogasch NC, Butler JE, Hayes M, Wilcox RA, Gandevia SC, Aoun K, Esterman A, Lewis SJG, Hall JM, Matar E, Godau J, Berg D, Plewnia C, von Thaler AK, Chiang C, and Double KL
- Subjects
- Humans, Aged, Motor Cortex diagnostic imaging, Parkinson Disease diagnostic imaging, Cortical Excitability
- Abstract
Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease., (© 2022 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)
- Published
- 2023
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37. Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord.
- Author
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Trist BG, Genoud S, Roudeau S, Rookyard A, Abdeen A, Cottam V, Hare DJ, White M, Altvater J, Fifita JA, Hogan A, Grima N, Blair IP, Kysenius K, Crouch PJ, Carmona A, Rufin Y, Claverol S, Van Malderen S, Falkenberg G, Paterson DJ, Smith B, Troakes C, Vance C, Shaw CE, Al-Sarraj S, Cordwell S, Halliday G, Ortega R, and Double KL
- Subjects
- Humans, Mutation, Spinal Cord pathology, Amyotrophic Lateral Sclerosis genetics, Protein Processing, Post-Translational, Superoxide Dismutase-1 genetics
- Abstract
Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro and in transgenic animal models of amyotrophic lateral sclerosis. Detailed examination of the protein in disease-affected tissues from amyotrophic lateral sclerosis patients, however, remains scarce. We used histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from amyotrophic lateral sclerosis cases and controls. Tissues were dissected into ventral and dorsal spinal cord grey matter to assess the specificity of alterations within regions of motor neuron degeneration. We provide evidence of the mislocalization and accumulation of structurally disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked and non-SOD1-linked familial amyotrophic lateral sclerosis cases, and sporadic amyotrophic lateral sclerosis cases, compared with control motor neurons. These changes were collectively associated with instability and mismetallation of enzymatically active SOD1 dimers, as well as alterations to SOD1 post-translational modifications and molecular chaperones governing SOD1 maturation. Atypical changes to SOD1 protein were largely restricted to regions of neurodegeneration in amyotrophic lateral sclerosis cases, and clearly differentiated all forms of amyotrophic lateral sclerosis from controls. Substantial heterogeneity in the presence of these changes was also observed between amyotrophic lateral sclerosis cases. Our data demonstrate that varying forms of SOD1 proteinopathy are a common feature of all forms of amyotrophic lateral sclerosis, and support the presence of one or more convergent biochemical pathways leading to SOD1 proteinopathy in amyotrophic lateral sclerosis. Most of these alterations are specific to regions of neurodegeneration, and may therefore constitute valid targets for therapeutic development., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2022
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38. Co-deposition of SOD1, TDP-43 and p62 proteinopathies in ALS: evidence for multifaceted pathways underlying neurodegeneration.
- Author
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Trist BG, Fifita JA, Hogan A, Grima N, Smith B, Troakes C, Vance C, Shaw C, Al-Sarraj S, Blair IP, and Double KL
- Subjects
- Animals, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Humans, Motor Neurons metabolism, Spinal Cord pathology, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, Superoxide Dismutase-1 genetics, Superoxide Dismutase-1 metabolism, Amyotrophic Lateral Sclerosis pathology
- Abstract
Multiple neurotoxic proteinopathies co-exist within vulnerable neuronal populations in all major neurodegenerative diseases. Interactions between these pathologies may modulate disease progression, suggesting they may constitute targets for disease-modifying treatments aiming to slow or halt neurodegeneration. Pairwise interactions between superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43) and ubiquitin-binding protein 62/sequestosome 1 (p62) proteinopathies have been reported in multiple transgenic cellular and animal models of amyotrophic lateral sclerosis (ALS), however corresponding examination of these relationships in patient tissues is lacking. Further, the coalescence of all three proteinopathies has not been studied in vitro or in vivo to date. These data are essential to guide therapeutic development and enhance the translation of relevant therapies into the clinic. Our group recently profiled SOD1 proteinopathy in post-mortem spinal cord tissues from familial and sporadic ALS cases, demonstrating an abundance of structurally-disordered (dis)SOD1 conformers which become mislocalized within these vulnerable neurons compared with those of aged controls. To explore any relationships between this, and other, ALS-linked proteinopathies, we profiled TDP-43 and p62 within spinal cord motor neurons of the same post-mortem tissue cohort using multiplexed immunofluorescence and immunohistochemistry. We identified distinct patterns of SOD1, TDP43 and p62 co-deposition and subcellular mislocalization between motor neurons of familial and sporadic ALS cases, which we primarily attribute to SOD1 gene status. Our data demonstrate co-deposition of p62 with mutant and wild-type disSOD1 and phosphorylated TDP-43 in familial and sporadic ALS spinal cord motor neurons, consistent with attempts by p62 to mitigate SOD1 and TDP-43 deposition. Wild-type SOD1 and TDP-43 co-deposition was also frequently observed in ALS cases lacking SOD1 mutations. Finally, alterations to the subcellular localization of the three proteins were tightly correlated, suggesting close relationships between the regulatory mechanisms governing the subcellular compartmentalization of these proteins. Our study is the first to profile spatial relationships between SOD1, TDP-43 and p62 pathologies in post-mortem spinal cord motor neurons of ALS patients, previously only studied in vitro. Our findings suggest interactions between these three key ALS-linked proteins are likely to modulate the formation of their respective proteinopathies, and perhaps the rate of motor neuron degeneration, in ALS patients., (© 2022. The Author(s).)
- Published
- 2022
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39. Empirical evidence for biometal dysregulation in Parkinson's disease from a systematic review and Bradford Hill analysis.
- Author
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Abdeen AH, Trist BG, and Double KL
- Abstract
The Bradford Hill model evaluates the causal inference of one variable on another by assessing whether evidence of the suspected causal variable aligns with a set of nine criteria proposed by Bradford Hill, each representing fundamental tenets of a causal relationship. The aim of this study was to use the Bradford Hill model of causation to assess the level of empirical evidence supporting our hypotheses that alterations to iron and copper levels, and iron- and copper-associated proteins and genes, contribute to Parkinson's disease etiology. We conducted a systematic review of all available articles published to September 2019 in four online databases. 8437 articles matching search criteria were screened for pre-defined inclusion and exclusion criteria. 181 studies met study criteria and were subsequently evaluated for study quality using established quality assessment tools. Studies meeting criteria for moderate to high quality of study design (n = 155) were analyzed according to the Bradford Hill model of causation. Evidence from studies considered of high quality (n = 73) supported a causal role for iron dysregulation in Parkinson's disease. A causal role for copper dysregulation in Parkinson's disease was also supported by high quality studies, although substantially fewer studies investigated copper in this disorder (n = 25) compared with iron. The available evidence supports an etiological role for iron and copper dysregulation in Parkinson's disease, substantiating current clinical trials of therapeutic interventions targeting alterations in brain levels of these metals in Parkinson's disease., (© 2022. The Author(s).)
- Published
- 2022
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40. A brief history of brain iron accumulation in Parkinson disease and related disorders.
- Author
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Foley PB, Hare DJ, and Double KL
- Subjects
- Brain, Humans, Iron, Substantia Nigra, Basal Ganglia Diseases, Parkinson Disease complications
- Abstract
Iron has a long and storied history in Parkinson disease and related disorders. This essential micronutrient is critical for normal brain function, but abnormal brain iron accumulation has been associated with extrapyramidal disease for a century. Precisely why, how, and when iron is implicated in neuronal death remains the subject of investigation. In this article, we review the history of iron in movement disorders, from the first observations in the early twentieth century to recent efforts that view extrapyramidal iron as a novel therapeutic target and diagnostic indicator., (© 2022. The Author(s).)
- Published
- 2022
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41. Native Separation and Metallation Analysis of SOD1 Protein from the Human Central Nervous System: a Methodological Workflow.
- Author
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Roudeau S, Trist BG, Carmona A, Davies KM, Halliday GM, Rufin Y, Claverol S, Van Malderen SJM, Falkenberg G, Double KL, and Ortega R
- Subjects
- Central Nervous System, Copper, Humans, Mutation, Superoxide Dismutase genetics, Superoxide Dismutase-1, Workflow, Amyotrophic Lateral Sclerosis, Zinc
- Abstract
Studies of the metal content of metalloproteins in tissues from the human central nervous system (CNS) can be compromised by preparative techniques which alter levels of, or interactions between, metals and the protein of interest within a complex mixture. We developed a methodological workflow combining size exclusion chromatography, native isoelectric focusing, and either proton or synchrotron X-ray fluorescence within electrophoresis gels to analyze the endogenous metal content of copper-zinc superoxide dismutase (SOD1) purified from minimal amounts (<20 mg) of post-mortem human brain and spinal cord tissue. Abnormal metallation and aggregation of SOD1 are suspected to play a role in amyotrophic lateral sclerosis and Parkinson's disease, but data describing SOD1 metal occupancy in human tissues have not previously been reported. Validating our novel approach, we demonstrated step-by-step metal preservation, preserved SOD1 activity, and substantial enrichment of SOD1 protein versus confounding metalloproteins. We analyzed tissues from nine healthy individuals and five CNS regions (occipital cortex, substantia nigra, locus coeruleus, dorsal spinal cord, and ventral spinal cord). We found that Cu and Zn were bound to SOD1 in a ratio of 1.12 ± 0.28, a ratio very close to the expected value of 1. Our methodological workflow can be applied to the study of endogenous native SOD1 in a pathological context and adapted to a range of metalloproteins from human tissues and other sources.
- Published
- 2021
- Full Text
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42. Superoxide Dismutase 1 in Health and Disease: How a Frontline Antioxidant Becomes Neurotoxic.
- Author
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Trist BG, Hilton JB, Hare DJ, Crouch PJ, and Double KL
- Subjects
- Biocatalysis, Enzyme Stability, Humans, Superoxide Dismutase-1 deficiency, Superoxide Dismutase-1 genetics, Superoxides metabolism, Antioxidants metabolism, Central Nervous System Diseases metabolism, Superoxide Dismutase-1 metabolism
- Abstract
Cu/Zn superoxide dismutase (SOD1) is a frontline antioxidant enzyme catalysing superoxide breakdown and is important for most forms of eukaryotic life. The evolution of aerobic respiration by mitochondria increased cellular production of superoxide, resulting in an increased reliance upon SOD1. Consistent with the importance of SOD1 for cellular health, many human diseases of the central nervous system involve perturbations in SOD1 biology. But far from providing a simple demonstration of how disease arises from SOD1 loss-of-function, attempts to elucidate pathways by which atypical SOD1 biology leads to neurodegeneration have revealed unexpectedly complex molecular characteristics delineating healthy, functional SOD1 protein from that which likely contributes to central nervous system disease. This review summarises current understanding of SOD1 biology from SOD1 genetics through to protein function and stability., (© 2020 The Authors. Published by Wiley-VCH GmbH.)
- Published
- 2021
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43. Measurement of the adult human midbrain with transcranial ultrasound.
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Aoun K, Double KL, Pearson-Dennett V, Yilmaz R, Berg D, and Todd G
- Subjects
- Adolescent, Adult, Amphetamine-Related Disorders diagnostic imaging, Female, Humans, Male, Methamphetamine, Middle Aged, Parkinson Disease diagnostic imaging, Young Adult, Mesencephalon diagnostic imaging, Substantia Nigra diagnostic imaging, Ultrasonography, Doppler, Transcranial
- Abstract
Background: Transcranial sonography is increasingly used to aid clinical diagnoses of movement disorders, for example, to identify an enlarged area of substantia nigra echogenicity in patients with Parkinson's disease., Objective: The current study investigated characteristics of the midbrain at the anatomical plane for quantification of substantia nigra echogenicity. METHODS: Area of substantia nigra echogenicity, cross-sectional area of the midbrain, and interpeduncular angle were quantified in two groups of adults aged 18-50 years: 47 healthy non-drug-using controls (control group) and 22 individuals with a history of methamphetamine use (methamphetamine group), a cohort with a high prevalence of enlarged substantia nigra echogenicity and thus risk of Parkinson's disease., Results: In the control group, cross-sectional area of the midbrain (4.47±0.44 cm2) and interpeduncular angle were unaffected by age, sex, or image acquisition side. In the methamphetamine group, cross-sectional midbrain area (4.72±0.60 cm2) and area of substantia nigra echogenicity were enlarged compared to the control group, and the enlargement was sex-dependent (larger in males than females). Whole midbrain area and interpeduncular angle were found to be weak predictors of area of substantia nigra echogenicity after accounting for group and sex., Conclusions: History of methamphetamine use is associated with an enlarged midbrain and area of substantia nigra echogenicity, and the abnormality is more pronounced in males than females. Thus, males may be more susceptible to methamphetamine-induced changes to the brainstem, and risk of Parkinson's disease, than females., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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44. Meta-Analysis of Copper and Iron in Parkinson's Disease Brain and Biofluids.
- Author
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Genoud S, Senior AM, Hare DJ, and Double KL
- Subjects
- Brain, Copper, Humans, Iron, Substantia Nigra, Parkinson Disease
- Abstract
Background: Variations in study quality and design complicate interpretation of the clinical significance of consistently reported changes in copper and iron levels in human Parkinson's disease brain and biofluids., Methods: We systematically searched literature databases for quantitative reports of biometal levels in the degenerating substantia nigra (SN), CSF, serum, and plasma in Parkinson's disease compared with healthy age-matched controls and assessed the quality of these publications. The primary outcomes of our analysis confirmed SN copper and iron levels are decreased and increased, respectively, in the Parkinson's disease brain. We applied a novel Quality Assessment Scale for Human Tissue to categorize the quality of individual studies and investigated the effects of study quality on our outcomes. We undertook a random-effects meta-analysis and meta-regression subgroup analysis., Results: In the 18 eligible studies identified (211 Parkinson's disease, 215 control cases), SN copper levels were significantly lower (d, -2.00; 95% CI, -2.81 to -1.19; P < 0.001), and iron levels were significantly higher (d, 1.31; 95% CI, 0.38-2.24; P < 0.01) in Parkinson's disease. No changes were detected in CSF, serum, or plasma for any metals (29 studies; 2443 Parkinson's disease and 2183 control cases) except serum iron, which was lower in Parkinson's disease (14 studies; 1177 Parkinson's disease and 1447 control cases)., Conclusions: Reductions in copper levels and elevations in iron were confirmed as characteristic of the degenerating SN of Parkinson's disease. Iron in serum was also changed, but in the opposite direction to that in the SN and to a lesser extent. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)
- Published
- 2020
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45. Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease.
- Author
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Trist BG, Hare DJ, and Double KL
- Subjects
- Animals, Calcium metabolism, Humans, Mitochondria metabolism, Mitochondria pathology, Parkinson Disease pathology, Substantia Nigra pathology, Aging metabolism, Cellular Senescence, Oxidative Stress, Parkinson Disease etiology, Parkinson Disease metabolism, Substantia Nigra metabolism
- Abstract
Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease-modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady-state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
- Published
- 2019
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46. Levels of glial cell line-derived neurotrophic factor are decreased, but fibroblast growth factor 2 and cerebral dopamine neurotrophic factor are increased in the hippocampus in Parkinson's disease.
- Author
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Virachit S, Mathews KJ, Cottam V, Werry E, Galli E, Rappou E, Lindholm P, Saarma M, Halliday GM, Shannon Weickert C, and Double KL
- Subjects
- Aged, Aged, 80 and over, Brain pathology, Brain-Derived Neurotrophic Factor metabolism, Corpus Striatum pathology, Dopamine metabolism, Female, Fibroblast Growth Factor 2 metabolism, Glial Cell Line-Derived Neurotrophic Factors metabolism, Hippocampus pathology, Humans, Intercellular Signaling Peptides and Proteins analysis, Intercellular Signaling Peptides and Proteins metabolism, Male, Neuroglia metabolism, Substantia Nigra pathology, Hippocampus metabolism, Nerve Growth Factors metabolism, Parkinson Disease metabolism
- Abstract
Growth factors can facilitate hippocampus-based learning and memory and are potential targets for treatment of cognitive dysfunction via their neuroprotective and neurorestorative effects. Dementia is common in Parkinson's disease (PD), but treatment options are limited. We aimed to determine if levels of growth factors are altered in the hippocampus of patients with PD, and if such alterations are associated with PD pathology. Enzyme-linked immunosorbent assays were used to quantify seven growth factors in fresh frozen hippocampus from 10 PD and nine age-matched control brains. Western blotting and immunohistochemistry were used to explore cellular and inflammatory changes that may be associated with growth factor alterations. In the PD hippocampus, protein levels of glial cell line-derived neurotrophic factor were significantly decreased, despite no evidence of neuronal loss. In contrast, protein levels of fibroblast growth factor 2 and cerebral dopamine neurotrophic factor were significantly increased in PD compared to controls. Levels of the growth factors epidermal growth factor, heparin-binding epidermal growth factor, brain-derived neurotrophic factor and mesencephalic astrocyte-derived neurotrophic factor did not differ between groups. Our data demonstrate changes in specific growth factors in the hippocampus of the PD brain, which potentially represent targets for modification to help attenuate cognitive decline in PD. These data also suggest that multiple growth factors and direction of change needs to be considered when approaching growth factors as a potential treatment for cognitive decline., (© 2019 International Society of Neuropathology.)
- Published
- 2019
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47. Expression of tyrosine hydroxylase isoforms and phosphorylation at serine 40 in the human nigrostriatal system in Parkinson's disease.
- Author
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Shehadeh J, Double KL, Murphy KE, Bobrovskaya L, Reyes S, Dunkley PR, Halliday GM, and Dickson PW
- Subjects
- Dopaminergic Neurons metabolism, Humans, Phosphorylation, Corpus Striatum metabolism, Parkinson Disease metabolism, Protein Isoforms metabolism, Substantia Nigra metabolism, Tyrosine 3-Monooxygenase metabolism
- Abstract
Tyrosine hydroxylase is the key enzyme controlling the synthesis of the catecholamines including dopamine. The breakdown of dopamine into toxic compounds has been suggested to have a key role in the degeneration of the dopaminergic neurons in Parkinson's disease. Humans are unique in containing four isoforms of tyrosine hydroxylase, but understanding of the role of these isoforms under normal conditions and in disease states is limited. The aim of this work was to determine the level and distribution of the four human isoforms in tissues from healthy controls and patients with Parkinson's disease. The results show that isoform 1 and isoform 2 are the major tyrosine hydroxylase isoforms in human brain, but that tyrosine hydroxylase isoform 2 is more abundant in the substantia nigra than the tyrosine hydroxylase isoform 1. The two minor isoforms, isoform 3 and isoform 4, are expressed at a proportionally higher level in the terminal field regions (caudate and putamen) compared to the substantia nigra. There was a selective loss of tyrosine hydroxylase isoform 1 in Parkinson's disease compared to age-matched controls and a corresponding increase in the proportion of tyrosine hydroxylase isoform 2. Phosphorylation of serine 40 was significantly increased in caudate, putamen and ventral tegmental area, but not in the substantia nigra, in Parkinson's disease brain. These results show a selective sparing of tyrosine hydroxylase isoform 2 in Parkinson's disease. Isoform 2 exhibits a reduced capacity for activation compared to isoform 1, which may account for the selective sparing of cells expressing isoform 2 in Parkinson's disease. Surviving neurons in Parkinson's disease brain exhibit a substantial increase in tyrosine hydroxylase phosphorylation consistent with a compensatory mechanism of increased dopamine synthesis in the terminal field regions., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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48. Reduction in IGF1 mRNA in the Human Subependymal Zone During Aging.
- Author
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Weissleder C, Barry G, Fung SJ, Wong MW, Double KL, Webster MJ, and Weickert CS
- Abstract
The cell proliferation marker, Ki67 and the immature neuron marker, doublecortin are both expressed in the major human neurogenic niche, the subependymal zone (SEZ), but expression progressively decreases across the adult lifespan (PMID: 27932973). In contrast, transcript levels of several mitogens (transforming growth factor α, epidermal growth factor and fibroblast growth factor 2) do not decline with age in the human SEZ, suggesting that other growth factors may contribute to the reduced neurogenic potential. While insulin like growth factor 1 (IGF1) regulates neurogenesis throughout aging in the mouse brain, the extent to which IGF1 and IGF family members change with age and relate to adult neurogenesis markers in the human SEZ has not yet been determined. We used quantitative polymerase chain reaction to examine gene expression of seven IGF family members [IGF1, IGF1 receptor, insulin receptor and high-affinity IGF binding proteins (IGFBPs) 2, 3, 4 and 5] in the human SEZ across the adult lifespan (n=50, 21-103 years). We found that only IGF1 expression significantly decreased with increasing age. IGFBP2 and IGFBP4 expression positively correlated with Ki67 mRNA. IGF1 expression positively correlated with doublecortin mRNA, whereas IGFBP2 expression negatively correlated with doublecortin mRNA. Our results suggest IGF family members are local regulators of neurogenesis and indicate that the age-related reduction in IGF1 mRNA may limit new neuron production by restricting neuronal differentiation in the human SEZ., Competing Interests: Disclosure Statement Cynthia Shannon Weickert is on an advisory board for Lundbeck, Australia Pty Ltd and in collaboration with Astellas Pharma Inc., Japan. All other authors have no conflicts of interest to disclose.
- Published
- 2019
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49. A Proposed Mechanism for Neurodegeneration in Movement Disorders Characterized by Metal Dyshomeostasis and Oxidative Stress.
- Author
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Trist BG, Hare DJ, and Double KL
- Subjects
- Animals, Homeostasis, Humans, Mutation, Superoxide Dismutase-1 genetics, Metals metabolism, Movement Disorders metabolism, Oxidative Stress, Superoxide Dismutase-1 metabolism
- Abstract
Shared molecular pathologies between distinct neurodegenerative disorders offer unique opportunities to identify common mechanisms of neuron death, and apply lessons learned from one disease to another. Neurotoxic superoxide dismutase 1 (SOD1) proteinopathy in SOD1-associated familial amyotrophic lateral sclerosis (fALS) is recapitulated in idiopathic Parkinson disease (PD), suggesting that these two phenotypically distinct disorders share an etiological pathway, and tractable therapeutic target(s). Despite 25 years of research, the molecular determinants underlying SOD1 misfolding and toxicity in fALS remain poorly understood. The absence of SOD1 mutations in PD highlights mounting evidence that SOD1 mutations are not the sole cause of SOD1 protein misfolding occasioning oligomerization and toxicity, reinforcing the importance of non-genetic factors, including protein metallation and post-translational modification in determining SOD1 stability and function. We propose that these non-genetic factors underlie the misfolding and dysfunction of SOD1 and other proteins in both PD and fALS, constituting a shared and tractable pathway to neurodegeneration., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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50. Accumulation of dysfunctional SOD1 protein in Parkinson's disease is not associated with mutations in the SOD1 gene.
- Author
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Trist BG, Fifita JA, Freckleton SE, Hare DJ, Lewis SJG, Halliday GM, Blair IP, and Double KL
- Subjects
- Cohort Studies, Humans, Mutation, Protein Aggregates genetics, Parkinson Disease enzymology, Parkinson Disease genetics, Superoxide Dismutase-1 genetics, Superoxide Dismutase-1 metabolism
- Published
- 2018
- Full Text
- View/download PDF
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