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Aggregated deposits of the protein α-synuclein and depleting levels of dopamine in the brain correlate with Parkinsons disease development. Treatments often focus on replenishing dopamine in the brain; however, the brain might not be the only site requiring attention. Aggregates of α-synuclein appear to accumulate in the gut years prior to the onset of any motor symptoms. Enteroendocrine cells (specialized gut epithelial cells) may be the source of intestinal α-synuclein, as they natively express this protein. Enteroendocrine cells are constantly exposed to gut bacteria and their metabolites because they border the gut lumen. These cells also express the dopamine metabolic pathway and form synapses with vagal neurons, which innervate the gut and brain. Through this connection, Parkinsons disease pathology may originate in the gut and spread to the brain over time. Effective therapeutics to prevent this disease progression are lacking due to a limited understanding of the mechanisms by which α-synuclein aggregation occurs in the gut. We previously proposed a gut bacterial metabolic pathway responsible for the initiation of α-synuclein aggregation that is dependent on the oxidation of dopamine. Here, we develop a new tool, a laser-induced graphene-based electrochemical sensor chip, to track α-synuclein aggregation and dopamine level over time. Using these sensor chips, we evaluated diet-derived catechols dihydrocaffeic acid and caffeic acid as potential inhibitors of α-synuclein aggregation. Our results suggest that these molecules inhibit dopamine oxidation. We also found that these dietary catechols inhibit α-synuclein aggregation in STC-1 enteroendocrine cells. These findings are critical next steps to reveal new avenues for targeted therapeutics to treat Parkinsons disease, specifically in the context of functional foods that may be used to reshape the gut environment.

To investigate physiological function of α-synuclein is important for understanding its pathophysiological mechanism in synucleinopathies including Parkinson's disease. Employing knockout mice, we found that Snac/α-synuclein deletion induced aberrant projection of olfactory sensory neurons and hyposmia. We identified 9 axon guidance associated differentially expressed proteins using iTRAQ based Liquid Chromatograph Mass Spectrometer. NCK2 is most significantly down-regulated protein among them. We further found that either α-synuclein deletion or NCK2 deficiency induced Eph A4 inactivation. Re-expressing Snac/α-synuclein in its knockout neurons reversed the down-regulation of NCK2, as well as the inactivation of EphA4. Overexpression of Snac/α-synuclein in α-synuclein deleted mice reversed the down-regulation of NCK2 and pEphA4, and improved the olfactory impairment of mice. Correlation analysis showed that there is a significant correlation between the protein level of α-synuclein, NCK2, and pEphA4, respectively. Nonetheless, immunoprecipitation analysis showed that NCK2 was associated with both EphA4 and Rho A, suggesting that NCK2 as a scaffolding protein to modulate Eph A4/Rho A pathway. Moreover, Rho A activity was significantly lower in α-synuclein deficient mice. Thus, α-synuclein regulates olfactory neurons projection through NCK2 dependent EphA4/Rho A pathway. Malfunction of α-synuclein because of deletion may cause aberrant olfactory neurons projection. This extended our knowledge of α-synuclein functions, which may explain why olfaction is usually impaired in some synucleinopathies. [ABSTRACT FROM AUTHOR]

Astrocyte‐microglia crosstalk is vital for neuronal survival and clearing aggregate accumulation in neurodegenerative diseases. While interleukin‐3 (IL‐3) has been reported to exert both protective and detrimental effects in neurodegenerative diseases, however, its role in α‐synuclein pathology remains unclear. In this study, it is found that astrocytic IL‐3 and microglial IL‐3R are positively responsive to α‐synuclein pathology in the brains of transgenic A53T Parkinson's disease (PD) mice and in an adeno‐associated virus (AAV)‐human α‐synuclein (AAV‐hα‐Syn)‐injected PD mouse model. Exogenous IL‐3 infusion reduces behavioral abnormities and nigrostriatal α‐synuclein pathology. Mechanistically, IL‐3 induces microglial phagocytosis of pathological α‐synuclein while simultaneously stimulating dopaminergic (DA) neurons to clear pathological α‐synuclein via induction of autophagy through the IFN‐β/Irgm1 pathway. Due to its limited efficiency in crossing the blood–brain barrier, a precise IL‐3 delivery strategy is developed by cross‐linking IL‐3 and RVG29 with PEG‐Linker (RVG‐modified IL‐3 nanogels—RVG‐IL3 NGs). Intravenous administration of RVG‐IL3 NGs shows efficient uptake by microglia and DA neurons within the brain. RVG‐IL3 NGs ameliorate motor deficits and pathological α‐synuclein by improving microglial and neuronal function in the AAV‐hα‐Syn mouse model of PD. Collectively, IL‐3 may represent a feasible therapeutic strategy for PD. [ABSTRACT FROM AUTHOR]

Astrocytes are the most abundant cells in the brain and show neuroprotective function in CNS and reactive astrocytes are characteristic in neurodegenerative diseases. The JAK2-STAT3 pathway plays a crucial role in the process of astrocyte activation. However, as a hallmark of Parkinson's disease, the change in α-syn under the influence of STAT3 inhibitor and the underlying cellular mechanisms remain elusive. Here, we show that PFF can induce an increase in α-syn in SVG p12 cells, which is further enhanced after the inhibition of STAT3. The underlying mechanisms involve the downregulation of autophagy levels and a concurrent decrease in lysosomal function after inhibition of STAT3. Additionally, we observed inhibition of STAT3 resulted in reduced exosome secretion in SVG p12 cells. This is attributed to alterations in SNARE, leading to impaired fusion between MVBs and the cell membrane, subsequently causing the accumulation of intracellular MVBs. Taken together, our data demonstrates that inhibition of STAT3 decreases both the autophagy and lysosome function, which may increase MVBs production. However, we found a potentially decreased exosome production that may be implicated with SNARE complex and need further exploration. [ABSTRACT FROM AUTHOR]

The Parkinson's disease protein, alpha-synuclein (α-syn/SNCA), is highly expressed in neurons and melanomas. The goal of this study was to reveal the mechanism(s) of α-syn's involvement in melanoma pathogenesis. To decipher the genes and pathways affected by α-syn, we conducted an RNA sequencing analysis of human SK-MEL-28 cells and several SK-MEL-28 SNCA-KO clones. We identified 1098 significantly up-regulated genes and 660 significantly down-regulated genes. Several of the upregulated genes are related to the immune system, i.e., the inflammatory response and the matrisome. We validated five upregulated genes (IL-1β, SAA1, IGFBP5, CXCL8, and CXCL10) by RT-qPCR and detected IGFBP5 and IL-1β in spent media of control and SNCA-KO cells. The levels of each of these secreted proteins were significantly higher in the spent media of the SNCA-KO clones than control cells. These secreted proteins quite likely activate the immune response against SNCA-KO cells. We suggest that, conversely, high levels of α-syn expression in melanoma cells helps the cells evade the immune system by inhibiting the secretion of these immune activating factors. [ABSTRACT FROM AUTHOR]

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by accumulation of α‐synuclein cross‐β amyloid filaments in the brain. Previous structural studies of these filaments by cryo‐electron microscopy (cryo‐EM) revealed three discrete folds distinct from α‐synuclein filaments associated with other neurodegenerative diseases. Here, we use cryo‐EM to identify a novel, low‐populated MSA filament subtype (designated Type I2) in addition to a predominant class comprising MSA Type II2 filaments. The 3.3‐Å resolution structure of the Type I2 filament reveals a fold consisting of two asymmetric protofilaments, one of which adopts a novel structure that is chimeric between two previously reported protofilaments. These results further define MSA‐specific folds of α‐synuclein filaments and have implications for designing MSA diagnostics and therapeutics. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), as a refractory neurological disorder with complex etiology, currently lacks effective therapeutic agents. Natural products (NPs), derived from plants, animals, or microbes, have shown promising effects in PD models through their antioxidative and anti-inflammatory properties, as well as the enhancement of mitochondrial homeostasis and autophagy. The misfolding and deposition of α-Synuclein (α-Syn), due to abnormal overproduction and impaired clearance, being central to the death of dopamine (DA) neurons. Thus, inhibiting α-Syn misfolding and aggregation has become a critical focus in PD discovery. This review highlights NPs that can reduce α-Syn aggregation by preventing its overproduction and misfolding, emphasizing their potential as novel drugs or adjunctive therapies for PD treatment, thereby providing further insights for clinical translation. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder marked by the loss of dopaminergic neurons and the formation of α-synuclein aggregates. Mitochondrial dysfunction and oxidative stress are pivotal in PD pathogenesis, with impaired mitophagy contributing to the accumulation of mitochondrial damage. Hederagenin (Hed), a natural triterpenoid, has shown potential neuroprotective effects; however, its mechanisms of action in PD models are not fully understood. We investigated the effects of Hed on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in SH-SY5Y cells by assessing cell viability, mitochondrial function, and oxidative stress markers. Mitophagy induction was evaluated using autophagy and mitophagy inhibitors and fluorescent staining techniques. Additionally, transgenic Caenorhabditis elegans (C. elegans) models of PD were used to validate the neuroprotective effects of Hed in vivo by focusing on α-synuclein aggregation, mobility, and dopaminergic neuron integrity. Hed significantly enhanced cell viability in 6-OHDA-treated SH-SY5Y cells by inhibiting cell death and reducing oxidative stress. It ameliorated mitochondrial damage, evidenced by decreased mitochondrial superoxide production, restored membrane potential, and improved mitochondrial morphology. Hed also induced mitophagy, as shown by increased autophagosome formation and reduced oxidative stress; these effects were diminished by autophagy and mitophagy inhibitors. In C. elegans models, Hed activated mitophagy and reduced α-synuclein aggregation, improved mobility, and mitigated the loss of dopaminergic neurons. RNA interference targeting the mitophagy-related genes pdr-1 and pink-1 partially reversed these benefits, underscoring the role of mitophagy in Hed's neuroprotective actions. Hed exhibits significant neuroprotective effects in both in vitro and in vivo PD models by enhancing mitophagy, reducing oxidative stress, and mitigating mitochondrial dysfunction. These findings suggest that Hed holds promise as a therapeutic agent for PD, offering new avenues for future research and potential drug development. [Display omitted] • Hederagenin (Hed) enhances mitophagy in SH-SY5Y cells and C. elegans. • Hed protects mitochondria and decreases oxidative stress via mitophagy induction. • Hed reduces α-synuclein aggregation and improves mobility in NL5901 worms. • Hed reduces the loss of neurons and improves mobility in 6-OHDA-induced BZ555 worms. • Hed exhibits neuroprotection via activating mitophagy through Pdr-1 and pink-1 genes. [ABSTRACT FROM AUTHOR]

Amyloid fibril formation is associated with various amyloidoses, including neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Despite the numerous studies on the inhibition of amyloid formation, the prevention and treatment of a majority of amyloid-related disorders are still challenging. In this study, we investigated the effects of various plant extracts on amyloid formation of α-synuclein. We found that the extracts from Eucalyptus gunnii are able to inhibit amyloid formation, and to disaggregate preformed fibrils, in vitro. The extract itself did not lead to cell damage. In the extract, miquelianin, which is a glycosylated form of quercetin and has been detected in the plasma and the brain, was identified and assessed to have a moderate inhibitory activity, compared to the effects of ellagic acid and quercetin, which are strong inhibitors for amyloid formation. The properties of miquelianin provide insights into the mechanisms controlling the assembly of α-synuclein in the brain. [ABSTRACT FROM AUTHOR]

Synucleinopathies are disorders characterized by the aggregation and deposition of pathological α-synuclein conformers. The underlying neurodegenerative processes begin years or decades before the onset of cardinal motor symptoms. This prodromal phase may manifest with various signs or symptoms. However, there are no current standardized laboratory tests to ascertain the progression and conversion of prodromal conditions such as mild cognitive impairment, isolated REM sleep behavior disorder or pure autonomic failure. The aim of this systematic review was to evaluate the diagnostic possibilities using human biofluids as source material to detect pathological α-synuclein in the prodromal phase of synucleinopathies. Our review identified eight eligible studies, that investigated pathological α-synuclein conformers using cerebrospinal fluid from patients with prodromal signs of synulceinopathies to differentiate this patient group from non-synucleinopathies, while only one study investigated this aspect using blood as medium. While previous studies clearly demonstrated a high diagnostic performance of α-synuclein seed amplification assays for differentiating synucleinopathies with Lewy bodies from healthy controls, only few analyses were performed focussing on individuals with prodromal disease. Nevertheless, results for the early detection of α-synuclein seeds using α-synuclein seed amplification assays were promising and may be of particular relevance for future clinical trials and clinical practice. [ABSTRACT FROM AUTHOR]

The recent development of new methods to detect misfolded α-synuclein (αSyn) aggregates in biofluids and tissue biopsies in the earliest Parkinson's disease (PD) phases is dramatically challenging the biological definition of PD. The αSyn seed amplification methods in cerebrospinal fluid (CSF) showed high sensitivity and specificity for early diagnosis of PD and Lewy bodies disorders. Several studies in isolated REM sleep behavior disorders and other at-risk populations also demonstrated a high prevalence of CSF αSyn positivity and its potential value in predicting the phenoconversion to clinically manifested diseases. Growing evidence exists for αSyn aggregates in olfactory mucosa, skin, and other tissues in subjects with PD or at-risk subjects. DOPA decarboxylase and numerous other candidates have been additionally proposed for either diagnostic or prognostic purposes in earliest PD phases. The newly described αSyn detection in blood, through its quantification in neuronally-derived exosome vesicles, represents a technical challenge that could open a new scenario for the biological diagnosis of PD. Despite this growing evidence in the field, most of method of αSyn detection and markers still need to be validated in ongoing longitudinal studies through an accurate assessment of different prodromal disease subtypes and scenarios before being definitively implemented in clinical settings. [ABSTRACT FROM AUTHOR]

Exidavnemab is a monoclonal antibody (mAb) with a high affinity and selectivity for pathological aggregated forms of α‐synuclein and a low affinity for physiological monomers, which is in clinical development as a disease‐modifying treatment for patients with synucleinopathies such as Parkinson's disease. Safety, tolerability, pharmacokinetics, immunogenicity, and exploratory biomarkers were assessed in two separate Phase 1 single ascending dose studies, including single intravenous (IV) (100 to 6000 mg) or subcutaneous (SC) (300 mg) administration of exidavnemab in healthy volunteers (HVs). Across the two studies, a total of 98 Western, Caucasian, Japanese, and Han Chinese HVs were enrolled, of which 95 completed the study. Exidavnemab was generally well tolerated. There were no serious adverse events or safety issues identified in laboratory analyses. Headache, asymptomatic COVID‐19, back pain, and post lumbar puncture syndrome were the most frequently reported treatment‐emergent adverse events. Following IV infusion, the pharmacokinetics of exidavnemab was approximately dose linear in the range 100‐6000 mg. The terminal half‐life was approximately 30 days, and the exposure was comparable across Western, Caucasian, Japanese, and Han Chinese volunteers. The absolute SC bioavailability was ∼71%. Cerebrospinal fluid exposure relative to serum after single dose was within the range expected for mAbs (approximately 0.2%). The anti‐drug antibody rates were low and there was no effect of immunogenicity on the pharmacokinetics or safety. Dose‐dependent reduction of free α‐synuclein in plasma was observed. In summary, exidavnemab was found to have an excellent pharmacokinetic profile and was well tolerated in HVs, supporting the continued clinical development. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests a potential role for infectious pathogens in the etiology of synucleinopathies, a group of age-related neurodegenerative disorders including Parkinson's disease (PD), multiple system atrophy and dementia with Lewy bodies. In this review, we discuss the link between infections and synucleinopathies from a historical perspective, present emerging evidence that supports this link, and address current research challenges with a focus on neuroinflammation. Infectious pathogens can elicit a neuroinflammatory response and modulate genetic risk in PD and related synucleinopathies. The mechanisms of how infections might be linked with synucleinopathies as well as the overlap between the immune cellular pathways affected by virulent pathogens and disease-related genetic risk factors are discussed. Here, an important role for α-synuclein in the immune response against infections is emerging. Critical methodological and knowledge gaps are addressed, and we provide new future perspectives on how to address these gaps. Understanding how infections and neuroinflammation influence synucleinopathies will be essential for the development of early diagnostic tools and novel therapies. Plain Language Summary: This review explores how infections might contribute to the development of Parkinson's disease and other synucleinopathies. It highlights evidence that microbial pathogens may trigger neurodegeneration by causing neuroinflammation. We emphasize the complex relationship between infections, genetics, and neurodegeneration, and discuss how understanding these connections could lead to earlier diagnosis and new treatments. In this review we also identify key knowledge gaps, and we suggest areas for future research. [ABSTRACT FROM AUTHOR]

The main genetic risk factors for Parkinson's disease (PD) are presently represented by variants in GBA1 gene encoding for the β‐glucocerebrosidase (GCase). Searching for a peripheral biomarker that can be used for selecting and monitoring patients in clinical trials targeting GBA1‐associated PD (GBA1‐PD) is a current challenge. We previously demonstrated that α‐synuclein oligomers expressed as proximity ligation assay (PLA) score in synaptic terminals of skin biopsy are a reliable biomarker for distinguishing idiopathic PD (iPD) from healthy controls (HC). This cross‐sectional study investigates an unexplored cohort of GBA1‐PD (n = 27) compared to 28 HC, and 36 iPD cases to (i) analyze α‐synuclein oligomers and quantify them throughout PLA score, (ii) investigate GCase expression in brain and synaptic terminals targeting the sweat gland, (iii) unravel indicators that could differentiate patients with specific GBA1 mutations. PLA score discriminates GBA1‐PD from HC with sensitivity = 88.9% (95% CI 70.84–97.65), specificity = 88.5% (95% CI 69.85–97.55), and PPV = 88.9% (95% CI 73.24–95.90), AUC value = 0.927 (95% CI 0.859–0.996). No difference was found between GBA1‐PD patients and iPD, suggesting a common pathological pathway based on α‐synuclein oligomers. GCase score did not differ in GBA1‐PD, iPD, and HC in the synaptic terminals, whereas a positive correlation was found between PLA score and GCase score. Moreover, a significant increase in synaptic density was observed in GBA1‐PD compared to iPD and HC (P < 0.0001). Employing ROC curve to discriminate GBA1‐PD from iPD, we found an AUC value for synaptic density = 0.855 (95% CI 0.749–0.961) with sensitivity = 85.2% (95% CI 66.27%–95.81%), specificity = 77.1% (95% CI 59.86%–89.58%), and PPV = 74.19% (60.53%–84.35%). The highest synaptic density values were observed in p.N409S patients. This work points out to the value of both PLA score and synaptic density in distinguishing GBA1‐PD from iPD and to their potential to stratify and monitor patients in the context of new pathway‐specific therapeutic options. [ABSTRACT FROM AUTHOR]

• PM 0.2 exposure induced the disorders of α-syn degradation in mice and astrocytes. • LAMP2-mediated autophagy-lysosome pathway was disturbed and underlied α-syn pathology induced by PM 0.2 exposure. • PP242 improved the disorder of α-syn through TFEB/LAMP2 pathway. Atmospheric particulate matter (PM) exacerbates the risk factor for Alzheimer's and Parkinson's diseases (PD) by promoting the alpha-synuclein (α-syn) pathology in the brain. However, the molecular mechanisms of astrocytes involvement in α-syn pathology underlying the process remain unclear. This study investigated PM with particle size <200 nm (PM 0.2) exposure-induced α-syn pathology in ICR mice and primary astrocytes, then assessed the effects of mammalian target of rapamycin inhibitor (PP242) in vitro studies. We observed the α-syn pathology in the brains of exposed mice. Meanwhile, PM 0.2 -exposed mice also exhibited the activation of glial cell and the inhibition of autophagy. In vitro study, PM 0.2 (3, 10 and 30 µg/mL) induced inflammatory response and the disorders of α-syn degradation in primary astrocytes, and lysosomal-associated membrane protein 2 (LAMP2)-mediated autophagy underlies α-syn pathology. The abnormal function of autophagy-lysosome was specifically manifested as the expression of microtubule-associated protein light chain 3 (LC3II), cathepsin B (CTSB) and lysosomal abundance increased first and then decreased, which might both be a compensatory mechanism to toxic α-syn accumulation induced by PM 0.2. Moreover, with the transcription factor EB (TFEB) subcellular localization and the increase in LC3II, LAMP2, CTSB, and cathepsin D proteins were identified, leading to the restoration of the degradation of α-syn after the intervention of PP242. Our results identified that PM 0.2 exposure could promote the α-syn pathological dysregulation in astrocytes, providing mechanistic insights into how PM 0.2 increases the risk of developing PD and highlighting TFEB/LAMP2 as a promising therapeutic target for antagonizing PM 0.2 toxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

INTRODUCTION: Subjective cognitive decline (SCD) may be an early marker of Alzheimer's disease (AD) pathology. Until recently, it was impossible to measure biomarkers specific for α‐synuclein pathology; therefore, its association with subjective reports of cognitive decline is unknown. METHODS: Alzheimer's Disease Neuroimaging Initiative participants without dementia (n = 918) were classified as positive or negative for amyloid beta (Aβ+ or Aβ−) and α‐synuclein (α‐syn+ or α‐syn−) biomarkers. Self‐ and study partner–reported cognitive decline was measured with the Everyday Cognition (ECog) questionnaire. RESULTS: Per self‐report, Aβ+/α‐syn+ had the greatest cognitive decline. Aβ−/α‐syn+ did not differ from Aβ−/α‐syn− across ECog scores. Study partner–reported results had a similar pattern, but Aβ+/α‐syn− and Aβ+/α‐syn+ did not differ across ECog scores. Mild cognitive impairment classification moderated the study partner–reported memory score. DISCUSSION: While α‐syn+ alone did not increase subjective reports of cognitive decline, Aβ+/α‐syn+ had the most self‐ and study partner–rated cognitive decline. Therefore, the presence of multiple pathologies was associated with greater SCD. Highlights: Cerebrospinal fluid α‐synuclein (α‐syn) seed amplification assay was used to determine α‐syn positivity.Amyloid beta (Aβ)−/α‐syn−, Aβ−/α‐syn+, Aβ+/α‐syn−, and Aβ+/α‐syn+ biomarker groups were created.Aβ+/α‐syn+ had greater subjective cognitive decline (SCD) than the other biomarker groups.Aβ−/α‐syn+ did not differ from Aβ−/α‐syn− across self‐ or study–partner reported SCD scores.Study partner–reported subjective memory results were largely driven by participants with mild cognitive impairment. [ABSTRACT FROM AUTHOR]

Introduction: The importance of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) diagnosis is rapidly increasing, and there is a growing interest in the use of CSF biomarkers in monitoring the response to therapy, especially in the light of newly available approaches to the therapy of neurodegenerative diseases. Areas covered: In this review we discuss the most relevant measures of neurodegeneration that are being used to distinguish patients with AD from healthy controls and individuals with mild cognitive impairment, in order to provide an overview of the latest information available in the scientific literature. We focus on markers related to amyloid processing, markers associated with neurofibrillary tangles, neuroinflammation, neuroaxonal injury and degeneration, synaptic loss and dysfunction, and markers of α-synuclein pathology. Expert opinion: In addition to neuropsychological evaluation, core CSF biomarkers (Aβ42, t-tau, and p-tau181) have been recommended for improvement of timely, accurate and differential diagnosis of AD, as well as to assess the risk and rate of disease progression. In addition to the core CSF biomarkers, various other markers related to synaptic dysfunction, neuroinflammation, and glial activation (neurogranin, SNAP-25, Nfl, YKL-40, TREM2) are now investigated and have yet to be validated for future potential clinical use in AD diagnosis. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder caused by the degeneration of dopaminergic neurons in the brain stem. PD is mostly sporadic, but familial PD (FPD) cases are recorded in different studies. The first gene mutation that is linked to FPD is α‐synuclein (α‐syn). It was then found that α‐syn is also accumulated in Lewy body (LB), a classical pathological hallmark in PD patients. Different studies have shown that α‐syn accumulation and aggregation can be a crucial factor contributing to the degeneration of dopaminergic neurons in PD. α‐syn has been found to be degraded by the ubiquitin proteasomal system (UPS) and autophagy–lysosomal pathway (ALP). In this study, we initially explored how α‐syn phosphorylation by GRK6, PLK2 and CK2α would facilitate its degradation in relation to the UPS or ALP. Unexpectedly, we found that the degradation of α‐syn through PLK2 phosphorylation could be modulated by UPS and ALP in a novel mechanism. Specially, attenuation of UPS could increase the amount of PLK2 and then could facilitate the phosphorylation and degradation of α‐syn through ALP. To test this further in vivo, we attenuate the proteasomal activity in a well‐established A53T α‐syn transgenic PD mouse model. We found that attenuation of proteasomal activity in the A53T α‐syn transgenic mice could reduce the accumulation of α‐syn in the striatum and midbrain. Based on our results, this study provides a new insight into how α‐syn is degraded through the UPS and ALP. [ABSTRACT FROM AUTHOR]

Protein aggregation, particularly the formation of amyloid fibrils, is associated with numerous human disorders, including Parkinson's disease. This neurodegenerative condition is characterised by the accumulation of α‐Synuclein amyloid fibrils within intraneuronal deposits known as Lewy bodies or neurites. C‐terminally truncated forms of α‐Synuclein are frequently observed in these inclusions in the brains of patients, and their increased aggregation propensity suggests a role in the disease's pathogenesis. This study demonstrates that the small molecule ZPD‐2 acts as a potent inhibitor of both the spontaneous and seeded amyloid polimerisation of C‐terminally truncated α‐Synuclein by interfering with early aggregation intermediates. This dual activity positions this molecule as a promising candidate for therapeutic development in treating synucleinopathies. [ABSTRACT FROM AUTHOR]

Background: Autophagy dysfunction in glial cells is implicated in the pathogenesis of Parkinson's disease (PD). The previous study reported that α-synuclein (α-Syn) disrupted autophagy in cultured microglia. However, the mechanism of microglial autophagy dysregulation is poorly understood. Methods: Two α-Syn-based PD models were generated via AAV-mediated α-Syn delivery into the mouse substantia nigra and striatal α-Syn preformed fibril (PFF) injection. The levels of microglial UNC-51-like kinase 1 (Ulk1) and other autophagy-related genes in vitro and in PD mice, as well as in the peripheral blood mononuclear cells of PD patients and healthy controls, were determined via quantitative PCR, western blotting and immunostaining. The regulatory effect of signal transducer and activator of transcription 1 (STAT1) on Ulk1 transcription was determined via a luciferase reporter assay and other biochemical studies and was verified through Stat1 knockdown or overexpression. The effect of α-Syn on glial STAT1 activation was assessed by immunohistochemistry and western blotting. Changes in microglial status, proinflammatory molecule expression and dopaminergic neuron loss in the nigrostriatum of PD and control mice following microglial Stat1 conditional knockout (cKO) or treatment with the ULK1 activator BL-918 were evaluated by immunostaining and western blotting. Motor behaviors were determined via open field tests, rotarod tests and balance beam crossing. Results: The transcription of microglial ULK1, a kinase that controls autophagy initiation, decreased in both in vitro and in vivo PD mouse models. STAT1 plays a critical role in suppressing Ulk1 transcription. Specifically, Stat1 overexpression downregulated Ulk1 transcription, while Stat1 knockdown increased ULK1 expression, along with an increase in LC3II and a decrease in the SQSTM1/p62 protein. α-Syn PFF caused toll-like receptor 4-dependent activation of STAT1 in microglia. Ablation of Stat1 alleviated the decrease in microglial ULK1 expression and disruption of autophagy caused by α-Syn PFF. Importantly, the ULK1 activator BL-918 and microglial Stat1 cKO attenuated neuroinflammation, dopaminergic neuronal damage and motor defects in PD models. Conclusions: These findings reveal a novel mechanism by which α-Syn impairs microglial autophagy and indicate that targeting STAT1 or ULK1 may be a therapeutic strategy for PD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive age-related neurodegenerative disorder affecting millions of people worldwide. Essentially, it is characterised by selective degeneration of dopamine neurons of the nigro-striatal pathway and intraneuronal aggregation of misfolded α-synuclein with formation of Lewy bodies and Lewy neurites. Moreover, specific small molecules of intermediary metabolism may have a definite pathophysiological role in PD. These include dopamine, levodopa, reduced glutathione, glutathione disulfide/oxidised glutathione, and the micronutrients thiamine and ß-Hydroxybutyrate. Recent research indicates that these small molecules can interact with α-synuclein and regulate its folding and potential aggregation. In this review, we discuss the current knowledge on interactions between α-synuclein and both the small molecules of intermediary metabolism in the brain relevant to PD, and many other natural and synthetic small molecules that regulate α-synuclein aggregation. Additionally, we analyse some of the relevant molecular mechanisms potentially involved. A better understanding of these interactions may have relevance for the development of rational future therapies. In particular, our observations suggest that the micronutrients ß-Hydroxybutyrate and thiamine might have a synergistic therapeutic role in halting or reversing the progression of PD and other neuronal α-synuclein disorders. [ABSTRACT FROM AUTHOR]

• PD-O-α-Syn and MSA-O-α-Syn are differentially phosphorylated at serine 129. • PD-O-α-Syn and MSA-O-α-Syn have different cytotoxicity and seeding activity. • PD-O-α-Syn and MSA-O-α-Syn cause distinct dopaminergic damage and motor disorders. Previous studies have shown that α-synuclein (α-Syn) aggregates derived from the brains of patients with Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit different phosphorylation, cytotoxicity, and seeding activity. However, the mechanism underlying the differences remains poorly understood. Here, recombinant human α-Syn was incubated in the plasma of patients with PD and MSA, and the oligomers formed in the plasma (PD-O-α-Syn and MSA-O-α-Syn) were purified and analyzed for their phosphorylation, cytotoxicity and seeding activity. In vitro assays revealed that both PD-O-α-Syn and MSA-O-α-Syn were phosphorylated at serine 129. However, the phosphorylation degree of MSA-O-α-Syn was significantly higher than that of PD-O-α-Syn. In addition, MSA-O-α-Syn exhibited stronger cytotoxicity and seeding activity compared with PD-O-α-Syn. In vivo experiments showed that mice receiving intrastriatal inoculation of MSA-O-α-Syn developed more severe motor dysfunction and dopaminergic degeneration than mice receiving intrastriatal inoculation of PD-O-α-Syn. Compared with the mice inoculated with PD-O-α-Syn, the mice inoculated with MSA-O-α-Syn accumulated more phosphorylated and oligomerized α-Syn in the striatum and brain regions (substantia nigra, hippocampus and prefrontal cortex) away from the inoculated site. The results obtained suggest that α-Syn oligomers formed in PD and MSA plasma are different in phosphorylation, cytotoxicity, and seeding activity. [ABSTRACT FROM AUTHOR]

Aims: Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs), primarily constituted of α‐synuclein (α‐Syn). Microglial cells exhibit specific reactivity toward misfolded proteins such as α‐Syn. However, the exact clearance mechanism and related molecular targets remain elusive. Methods: BV2 cells, primary microglia from wild‐type and MT1 knockout mice, and primary cortical neurons were utilized as experimental models. The study investigated relevant mechanisms by modulating microglial MT1 expression through small RNA interference (RNAi) and lentiviral overexpression techniques. Furthermore, pathological aggregation of α‐Syn was induced using pre‐formed fibrils (PFF) α‐Syn. Co‐immunoprecipitation, immunofluorescence, Western blot (WB), and quantitative real‐time PCR were used to elucidate the mechanisms of molecular regulation. Results: In this study, we elucidated the regulatory role of the melatonin receptor 1 (MT1) in the microglial phagocytic process. Following MT1 knockout, the ability of microglial cells to engulf latex beads and zymosan particles decreased, subsequently affecting the phagocytic degradation of fibrillar α‐Syn by microglial cells. Furthermore, the loss of MT1 receptors in microglial cells exacerbates the aggregation of α‐Syn in neurons induced by pre‐formed fibrils (PFF) α‐Syn. Mechanistically, MT1 influences the phagocytic function of microglial cells by regulating the Rubicon‐dependent LC3‐associated phagocytosis (LAP) pathway. Conclusion: Taken together, the results suggest the neuroprotective function of microglial cells in clearing α‐Syn through MT1‐mediated LAP, highlighting the potential key role of MT1 in pathogenic mechanisms associated with α‐Syn. [ABSTRACT FROM AUTHOR]

Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α‐synuclein (αSyn) aggregation in affected brain regions. However, the role of αSyn in the pathogenesis and evolution of the disease remains unclear, despite vast research efforts of more than a quarter century. A better understanding of the role of αSyn, either primary or secondary, is critical for developing disease‐modifying therapies. Previous attempts to hone this research have been challenged by experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society (MDS) charged a panel of experts in the field to discuss current scientific priorities and identify research strategies with potential for a breakthrough. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Methamphetamine (METH) is a drug of abuse, which induces behavioral sensitization following repeated doses. Since METH alters blood pressure, in the present study we assessed whether systolic and diastolic blood pressure (SBP and DBP, respectively) are sensitized as well. In this context, we investigated whether alterations develop within A1/C1 neurons in the vasomotor center. C57Bl/6J male mice were administered METH (5 mg/kg, daily for 5 consecutive days). Blood pressure was measured by tail-cuff plethysmography. We found a sensitized response both to SBP and DBP, along with a significant decrease of catecholamine neurons within A1/C1 (both in the rostral and caudal ventrolateral medulla), while no changes were detected in glutamic acid decarboxylase. The decrease of catecholamine neurons was neither associated with the appearance of degeneration-related marker Fluoro-Jade B nor with altered expression of α-synuclein. Rather, it was associated with reduced free radicals and phospho-cJun and increased heat shock protein-70 and p62/sequestosome within A1/C1 cells. Blood pressure sensitization was not associated with altered arterial reactivity. These data indicate that reiterated METH administration may increase blood pressure persistently and may predispose to an increased cardiovascular response to METH. These data may be relevant to explain cardiovascular events following METH administration and stressful conditions. [ABSTRACT FROM AUTHOR]

Our previous cryogenic electron microscopy (cryoEM) analysis showed that the core structures of α-synuclein filaments accumulated in brains of patients diagnosed with dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) patients are different. We analyzed the post-translational modifications (PTMs) in these filaments , and examined their relationship with the core filament structures and pathological features. Besides the common PTMs in MSA and DLB filaments, acetylation, methylation, oxidation and phosphorylation were frequently detected in MSA filaments, but not in DLB filaments. Furthermore, in DLB filament cases, the processing occurred at the C-terminal side of Asp at 119 residue and Asn at 122 residue, while in MSA cases, the processing occurred at multiple sites between residues 109–123. We have previously reported that PTMs in tau filaments depend on the filament core structure. This was considered to apply to α-synuclein filaments as well. As an example, PTMs including processing sites detected in α-synuclein filaments in early-onset DLB (an atypical form, now named juvenile-onset α-synucleinopathy) brain also supported this idea. These suggests that PTMs appeared to be closely related to the specific filament core structures. [ABSTRACT FROM AUTHOR]

"Path to a good mood lies through the gut." This statement seems to imply that it has long been believed that the gut is connected with the brain. Research has shown that eating food activates the reward system and releases dopamine (DA), establishing a link between the peripheral and central nervous system. At the same time, researchers also trust that the gut is involved in the onset of many diseases, including Parkinson's disease (PD), in which gastrointestinal dysfunction is considered a prevalent symptom. Reports suggest that PD starts from the gut and reaches the brain via the vagus nerve. Recent studies have revealed an intriguing interaction between the gut and brain, which links gut dysbiosis to the etiology of PD. This review aims to explore the mechanistic pathway how reactive oxygen species (ROS) generation in the gut affects the makeup and operation of the dopamine circuitry in the brain. Our primary concern is ROS generation in the gut, which disrupts the gut microbiome (GM), causing α-synuclein accumulation and inflammation. This trio contributes to the loss of DA neurons in the brain, resulting in PD development. This review also compiles pre-clinical and clinical studies on antioxidants, demonstrating that antioxidants reduce ROS and increase DA levels. Collectively, the study highlights the necessity of comprehending the gut–brain axis for unraveling the riddles of PD pathogenesis and considering new therapeutic approaches. [ABSTRACT FROM AUTHOR]

[Display omitted] • We developed an aggressive multiple system atrophy-cerebellar variant mouse model. • In mice, human α-synuclein was expressed in oligodendrocytes via Tet-Off regulation. • We observed age-dependent phosphorylated α-synuclein deposition in glia and neurons. • Marked microglial and astrocytic reaction with inflammation in demyelinated lesions. • α-Synuclein oligomers spread from oligodendrocytes to astrocytes and neurons. Multiple system atrophy (MSA) is a severe α-synucleinopathy facilitated by glial reactions; the cerebellar variant (MSA-C) preferentially involves olivopontocerebellar fibres with conspicuous demyelination. A lack of aggressive models that preferentially involve olivopontocerebellar tracts in adulthood has hindered our understanding of the mechanisms of demyelination and neuroaxonal loss, and thus the development of effective treatments for MSA. We therefore aimed to develop a rapidly progressive mouse model that recaptures MSA-C pathology. We crossed Plp1 -tTA and tetO- SNCA*A53T mice to generate Plp1 -tTA::tetO- SNCA*A53T bi-transgenic mice, in which human A53T α-synuclein—a mutant protein with enhanced aggregability—was specifically produced in the oligodendrocytes of adult mice using Tet-Off regulation. These bi-transgenic mice expressed mutant α-synuclein from 8 weeks of age, when doxycycline was removed from the diet. All bi-transgenic mice presented rapidly progressive motor deterioration, with wide-based ataxic gait around 22 weeks of age and death around 30 weeks of age. They also had prominent demyelination in the brainstem/cerebellum. Double immunostaining demonstrated that myelin basic protein was markedly decreased in areas in which SM132, an axonal marker, was relatively preserved. Demyelinating lesions exhibited marked ionised calcium-binding adaptor molecule 1-, arginase-1-, and toll-like receptor 2-positive microglial reactivity and glial fibrillary acidic protein-positive astrocytic reactivity. Microarray analysis revealed a strong inflammatory response and cytokine/chemokine production in bi-transgenic mice. Neuronal nuclei-positive neuronal loss and patchy microtubule-associated protein 2-positive dendritic loss became prominent at 30 weeks of age. However, a perceived decrease in tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta in bi-transgenic mice compared with wild-type mice was not significant, even at 30 weeks of age. Wild-type, Plp1 -tTA, and tetO- SNCA*A53T mice developed neither motor deficits nor demyelination. In bi-transgenic mice, double immunostaining revealed human α-synuclein accumulation in neurite outgrowth inhibitor A (Nogo-A)-positive oligodendrocytes beginning at 9 weeks of age; its expression was further increased at 10 to 12 weeks, and these increased levels were maintained at 12, 24, and 30 weeks. In an α-synuclein-proximity ligation assay, α-synuclein oligomers first appeared in brainstem oligodendrocytes as early as 9 weeks of age; they then spread to astrocytes, neuropil, and neurons at 12 and 16 weeks of age. α-Synuclein oligomers in the brainstem neuropil were most abundant at 16 weeks of age and decreased thereafter; however, those in Purkinje cells successively increased until 30 weeks of age. Double immunostaining revealed the presence of phosphorylated α-synuclein in Nogo-A-positive oligodendrocytes in the brainstem/cerebellum as early as 9 weeks of age. In quantitative assessments, phosphorylated α-synuclein gradually and successively accumulated at 12, 24, and 30 weeks in bi-transgenic mice. By contrast, no phosphorylated α-synuclein was detected in wild-type, tetO- SNCA*A53T , or Plp1 -tTA mice at any age examined. Pronounced demyelination and tubulin polymerisation, promoting protein-positive oligodendrocytic loss, was closely associated with phosphorylated α-synuclein aggregates at 24 and 30 weeks of age. Early inhibition of mutant α-synuclein expression by doxycycline diet at 23 weeks led to fully recovered demyelination; inhibition at 27 weeks led to persistent demyelination with glial reactions, despite resolving phosphorylated α-synuclein aggregates. In conclusion, our bi-transgenic mice exhibited progressively increasing demyelination and neuroaxonal loss in the brainstem/cerebellum, with rapidly progressive motor deterioration in adulthood. These mice showed marked microglial and astrocytic reactions with inflammation that was closely associated with phosphorylated α-synuclein aggregates. These features closely mimic human MSA-C pathology. Notably, our model is the first to suggest that α-synuclein oligomers may spread from oligodendrocytes to neurons in transgenic mice with human α-synuclein expression in oligodendrocytes. This model of MSA is therefore particularly useful for elucidating the in vivo mechanisms of α-synuclein spreading from glia to neurons, and for developing therapies that target glial reactions and/or α-synuclein oligomer spreading and aggregate formation in MSA. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Frontotemporal dementia (FTD) is characterized by phenotypic and genetic heterogeneities. However, reports on the large Chinese FTD cohort are lacking. METHODS: Two hundred forty‐eight patients with FTD were enrolled. All patients and 2010 healthy controls underwent next generation sequencing. Plasma samples were analyzed for glial fibrillary acidic protein (GFAP), α‐synuclein (α‐syn), neurofilament light chain (NfL), and phosphorylated tau protein 181 (p‐tau181). RESULTS: Gene sequencing identified 48 pathogenic or likely pathogenic mutations in a total of 19.4% of patients with FTD (48/248). The most common mutation was the C9orf72 dynamic mutation (5.2%, 13/248). Significantly increased levels of GFAP, α‐syn, NfL, and p‐tau181 were detected in patients compared to controls (all p < 0.05). GFAP and α‐syn presented better performance for diagnosing FTD. DISCUSSION: We investigated the characteristics of phenotypic and genetic spectrum in a large Chinese FTD cohort, and highlighted the utility of plasma biomarkers for diagnosing FTD. Highlights: This study used a frontotemporal dementia (FTD) cohort with a large sample size in Asia to update and reveal the clinical and genetic spectrum, and explore the relationship between multiple plasma biomarkers and FTD phenotypes as well as genotypes.We found for the first time that the C9orf72 dynamic mutation frequency ranks first among all mutations, which broke the previous impression that it was rare in Asian patients.Notably, it was the first time the C9orf72 G4C2 repeat expansion had been identified via whole‐genome sequencing data, and this was verified using triplet repeat primed polymerase chain reaction (TP‐PCR).We analyzed the diagnostic accuracy of four plasma biomarkers (glial fibrillary acidic protein [GFAP], α‐synuclein [α‐syn], neurofilament light chain [NfL], and phosphorylated tau protein 181 [p‐tau181]) at the same time, especially for α‐syn being included in the FTD cohort for the first time, and found GFAP and α‐syn had the highest diagnostic accuracy for FTD and its varied subtypes. [ABSTRACT FROM AUTHOR]

Background: Impulse control disorders (ICDs) are an increasingly recognized complication in Parkinson disease (PD). The pathogenesis of ICDs is currently unclear. Few genetic studies have been conducted in this area. Objective: We aimed to ascertain the correlation between APOE and ICDs, and identify clinical predictors of ICDs in PD. Methods: This study included 287 PD patients from the Parkinson's Progression Markers Initiative. They were followed up to investigate the progression of ICDs over a period of 5 years. The cumulative incidence of ICDs and potential risk factors were evaluated using Kaplan-Meier and Cox regression analyses. Results: 44.3% (31/70) patients with APOE ɛ4 and 32.3% (70/217) patients without APOE ɛ4 developed ICDs during the five-year follow up period. There were significant differences between the PD with and without ICDs development group in age, MSEADLG score, ESS score, GDS score, and STAI score at baseline. In multivariable Cox regression analysis, APOE ε4 (HR = 1.450, p = 0.048) and STAI score (HR = 1.017, p = 0.001) were predictors of the development of ICDs. Patients with APOE ɛ4 group showed significantly lower CSF Aβ42 and CSF α-syn level than patients without APOE ɛ4 group at baseline. In patients with APOE ɛ4 group, the "low α-syn level" group and the "low ptau/tau ratio" group had a significantly higher incidence of ICDs, respectively. Conclusions: This study provides important insights into the potential role of the APOE gene in the development of ICDs in PD. Further studies are needed to confirm our findings and to investigate the underlying mechanisms in more detail. [ABSTRACT FROM AUTHOR]

Postencephalitic parkinsonism (PEP) is suggested to show a virus-induced pathology, which is different from classical idiopathic Parkinson's disease (PD) as there is no α-synuclein/Lewy body pathology. However, PEP shows a typical clinical representation of motor disturbances. In addition, compared to PD, there is no iron-induced pathology. The aim of this preliminary study was to compare PEP with PD regarding iron-induced pathology, using histochemistry methods on paraffin-embedded post-mortem brain tissue. In the PEP group, iron was not seen, except for one case with sparse perivascular depositions. Rather, PEP offers a pathology related to tau-protein/neurofibrillary tangles, with mild to moderate memory deficits only. It is assumed that this virus-induced pathology is due to immunological dysfunctions causing (neuro)inflammation-induced neuronal network disturbances as events that trigger clinical parkinsonism. The absence of iron deposits implies that PEP cannot be treated with iron chelators. The therapy with L-Dopa is also not an option, as L-Dopa only leads to an initial slight improvement in symptoms in isolated cases. [ABSTRACT FROM AUTHOR]

[Display omitted] • Red emissive fluorescent amphiphilic carbon dots (CL-9) were designed. • The ternary carbon source was used. • CL-9 exerted turn-on red fluorescence towards α-synuclein fibrils. • CL-9 possessed good anti-photobleaching resistance, biocompatibility and high sensitivity. • CL-9 succeeded in imaging α-synuclein fibrils in vivo. The misfolding and aggregation of α -synuclein monomers usually cause the occurrence and development of Parkinson's disease (PD). It is important to develop effective methods for detection of α -synuclein aggregates. Carbon dots (CDs) could be the potential fluorescence probe for this purpose owing to their appreciated optical properties. However, undefined structure of CDs and complicated three-dimensional structure of protein severely hindered the design of fluorescence probe towards protein aggregates. Herein, a red emissive fluorescent amphiphilic CD, named as CL-9, was designed with a high sensitivity to α -synuclein fibrils by a one-step heating process, using the ternary carbon source, including Congo red, l -tryptophan and urea. The CL-9 exhibited turn-on red emissive fluorescence towards α -synuclein fibril, but remained no change towards its monomer. Compared with the original Congo red dye, CL-9 exhibited stronger turn-on red fluorescence towards α -synuclein fibrils with better anti-photobleaching resistance, biocompatibility and signal-to-noise ratio. The CL-9 was successful as a fluorescent probe to image α -synuclein fibrils in NL-5901 C. elegans. The present study provided a feasible approach using the multiple carbon sources to construct the CDs based fluorescence probe targeting amyloid proteins. [ABSTRACT FROM AUTHOR]

Background: GALNTs (UDP-GalNAc; polypeptide N-acetylgalactosaminyltransferases) initiate mucin-type O-GalNAc glycosylation by adding N-GalNAc to protein serine/threonine residues. Abnormalities in O-GalNAc glycosylation are involved in various disorders such as Parkinson's disease (PD), a neurodegenerative disorder. GALNT9 is potentially downregulated in PD patients. Methods: To determine whether GALNT9 enrichment ameliorates cytotoxicity related to PD-like variations, a pcDNA3.1-GALNT9 plasmid was constructed and transfected into SH-SY5Y cells to establish a GALNT9-overexpressing cell model. Results: Downregulation of GALNT9 and O-GalNAc glycosylation was confirmed in our animal and cellular models of PD-like variations. GALNT9 supplementation greatly attenuated cytotoxicity induced by MPP+ (1-Methyl-4-phenylpyridinium iodide) since it led to increased levels of tyrosine hydroxylase and dopamine, reduced rates of apoptosis, and significantly ameliorated MPP+-induced mitochondrial dysfunction by alleviating abnormal levels of mitochondrial membrane potential and reactive oxygen species. A long-lasting mPTP (mitochondrial permeability transition pores) opening and calcium efflux resulted in significantly lower activity in the cytochrome C-associated apoptotic pathway and mitophagy process, signifying that GALNT9 supplementation maintained neuronal cell health under MPP+ exposure. Additionally, it was found that glycans linked to proteins influenced the formation of protein aggregates containing α-synuclein, and GALNT9 supplement dramatically reduced such insoluble protein aggregations under MPP+ treatment. Glial GALNT9 predominantly appears under pathological conditions like PD-like variations. Conclusions: GALNT9 enrichment improved cell survival, and glial GALNT9 potentially represents a pathogenic index for PD patients. This study provides insights into the development of therapeutic strategies for the treatment of PD. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons and the accumulation of Lewy-body protein aggregates containing misfolded α-synuclein (α-syn) in a phosphorylated form. The lack of effective models for drug screens has hindered drug development studies for PD. However, the recent development of in vitro brain-like organoids provides a new opportunity for evaluating therapeutic agents to slow the progression of this chronic disease. Methods: In this study, we used a 3D brain-like organoid model to investigate the potential of repurposing Tilorone, an anti-viral drug, for impeding the propagation of α-synucleinopathy. We assessed the effect of Tilorone on the uptake of fluorescently labeled α-syn preformed fibrils (sPFF) and sPFF-induced apoptosis using confocal microscopy. We also examined Tilorone's impact on the phosphorylation of endogenous α-syn induced by pathogenic sPFF by immunoblotting midbrain-like organoid extracts. Additionally, quantitative RT-PCR and proteomic profiling of sPFF-treated organoids were conducted to evaluate the global impact of Tilorone treatment on tissue homeostasis in the 3D organoid model. Results: Tilorone inhibits the uptake of sPFF in both mouse primary neurons and human midbrain-like organoids. Tilorone also reduces the phosphorylation of endogenous α-syn induced by pathogenic α-syn fibrils and mitigates α-syn fibril-induced apoptosis in midbrain-like organoids. Proteomic profiling of fibril-treated organoids reveals substantial alterations in lipid homeostasis by α-syn fibrils, which are reversed by Tilorone treatment. Given its safety profile in clinics, Tilorone may be further developed as a therapeutic intervention to alleviate the propagation of synucleinopathy in PD patients. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is characterized by the accumulation of misfolded α-synuclein protein and the loss of dopaminergic neurons in the substantia nigra. Abnormal α-synuclein aggregates form toxic Lewy bodies, ultimately inducing neuronal injury. Mitochondrial dysfunction was reported to be involved in the neurotoxicity of α-synuclein aggregates in PD. However, the specific mechanism by which abnormal α-synuclein aggregates cause mitochondrial disorders remains poorly defined. Previously, we found that cofilin-1, a member of the actin-binding protein, regulates α-synuclein pathogenicity by promoting its aggregation and spreading in vitro and in vivo. In this study, we further investigated the eect of cofilin-1 on α-synuclein induced mitochondrial damage. We discovered that α-synuclein aggregates accelerate the translocation of cofilin-1 to mitochondria, promote its combination with the mitochondrial outer membrane receptor Tom 20, and ultimately activate the oxidative damage and apoptosis pathway in mitochondria. All these results demonstrate the important regulatory role of cofilin-1 in the mitochondrial neurotoxicity of pathological α-synuclein during the progression of PD [ABSTRACT FROM AUTHOR]

Glucocerebrosidase 1 (GBA1) mutations are the most important genetic risk factors for Parkinson's disease (PD). Clinically, mild (e.g., p.N370S) and severe (e.g., p.L444P and p.D409H) GBA1 mutations have different PD phenotypes, with differences in age at disease onset, progression, and the severity of motor and non‐motor symptoms. We hypothesize that GBA1 mutations cause the accumulation of α‐synuclein by affecting the cross‐talk between cellular protein degradation mechanisms, leading to neurodegeneration. Accordingly, we tested whether mild and severe GBA1 mutations differentially affect the degradation of α‐synuclein via the ubiquitin–proteasome system (UPS), chaperone‐mediated autophagy (CMA), and macroautophagy and differentially cause accumulation and/or release of α‐synuclein. Our results demonstrate that endoplasmic reticulum (ER) stress and total ubiquitination rates were significantly increased in cells with severe GBA1 mutations. CMA was found to be defective in induced pluripotent stem cell (iPSC)‐derived dopaminergic neurons with mild GBA1 mutations, but not in those with severe GBA1 mutations. When examining macroautophagy, we observed reduced formation of autophagosomes in cells with the N370S and D409H GBA1 mutations and impairments in autophagosome–lysosome fusion in cells with the L444P GBA1 mutation. Accordingly, severe GBA1 mutations were found to trigger the accumulation and release of oligomeric α‐synuclein in iPSC‐derived dopaminergic neurons, primarily as a result of increased ER stress and defective macroautophagy, while mild GBA1 mutations affected CMA, which is mainly responsible for the degradation of the monomeric form of α‐synuclein. Overall, our findings provide new insight into the molecular basis of the clinical variability in PD associated with different GBA1 mutations. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD), the most prevalent type of Parkinsonism, is a progressive neurological condition characterized by a range of motor and non‐motor symptoms. The complicated etiology of PD is thought to involve a summation of aging, genetic predisposition, and environmental variables. However, the α‐synuclein protein plays a significant role in the disease's pathophysiology. Materials and methods: The UAS‐α‐Syn and Ddc‐Gal4 strains were crossed to produce offspring referred to as PD flies. The entire population of flies was divided into five groups, each having about 100 flies and five replicates. The control group (w1118) and the PD group not receiving treatment were exposed to lauric acid (LA)/levodopa (LD)‐free diet, while the PD groups that received treatments were fed with either a 250 mg/kg LA diet, a 250 mg/kg LD diet, or a combination of the two for 21 days. Longevity, geotaxis, and olfactory assays were performed in addition to other biochemical tests. Results: As a result of the overexpression of α‐synuclein, the locomotive capacity, lifespan, and antioxidant status were all significantly (p <.05) reduced, and the apoptotic and neuroinflammatory activities were increased. Nevertheless, the majority of the treated flies improved significantly (p <.05). Conclusion: LA, whether combined with LD or not, elicited a significant response in α‐synuclein/dopa decarboxylase genetically modified Drosophila melanogaster Parkinsonism models. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) stands as the second most common neurological disorder after Alzheimer's disease, primarily affecting the elderly population and significantly compromising their quality of life. The precise etiology of PD remains elusive, but recent research has shed light on potential factors, including the formation of α‐synuclein aggregates, oxidative stress, neurotransmitter imbalances, and dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc) region of the brain, culminating in motor symptoms such as bradykinesia, akinesia, tremors, and rigidity. Monoamine oxidase (MAO) is an essential enzyme, comprising two isoforms, MAO‐A and MAO‐B, responsible for the oxidation of monoamines such as dopamine. Increased MAO‐B activity is responsible for decreased dopamine levels in the SNpc region of mid brain which is remarkably associated with the pathogenesis of PD‐like manifestations. Inhibitors of MAO‐B enhance striatal neuronal responses to dopamine, making them valuable in treating PD, which involves dopamine deficiency. Clinically approved MAO‐B inhibitors such as selegiline, L‐deprenyl, pargyline, and rasagiline are employed in the management of neurodegenerative conditions associated with PD. Current therapeutic interventions including MAO‐B inhibitors for PD predominantly aim to alleviate these motor symptoms but often come with a host of side effects that can be particularly challenging for the patients. While effective, they have limitations, prompting a search for alternative treatments, there is a growing interest in exploring natural products notably flavonoids as potential sources of novel MAO‐B inhibitors. In line with that, the present review focuses on natural flavonoids of plant origin that hold promise as potential candidates for the development of novel MAO‐B inhibitors. The discussion encompasses both in vitro and in vivo studies, shedding light on their potential therapeutic applications. Furthermore, this review underscores the significance of exploring natural products as valuable reservoirs of MAO‐B inhibitors, offering new avenues for drug development and addressing the pressing need for improved treatments in PD‐like pathological conditions. The authors of this review majorly explore the neuroprotective potential of natural flavonoids exhibiting notable MAO‐B inhibitory activity and additionally multi‐targeted approaches in the treatment of PD with clinical evidence and challenges faced in current therapeutic approaches. [ABSTRACT FROM AUTHOR]

A presynaptic protein called α-synuclein plays a crucial role in synaptic function and neurotransmitter release. However, its misfolding and aggregation have been implicated in a variety of neurodegenerative diseases, particularly Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Emerging evidence suggests that α-synuclein interacts with various cellular pathways, including mitochondrial dysfunction, oxidative stress, and neuroinflammation, which contributes to neuronal cell death. Moreover, α-synuclein has been involved in the propagation of neurodegenerative processes through prion-like mechanisms, where misfolded proteins induce similar conformational changes in neighboring neurons. Understanding the multifaced roles of α-synuclein in neurodegeneration not only aids in acquiring more knowledge about the pathophysiology of these diseases but also highlights potential biomarkers and therapeutic targets for intervention in alpha-synucleinopathies. In this review, we provide a summary of the mechanisms by which α-synuclein contributes to neurodegenerative processes, focusing on its misfolding, oligomerization, and the formation of insoluble fibrils that form characteristic Lewy bodies. Furthermore, we compare the potential value of α-synuclein species in diagnosing and differentiating selected neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of α-synuclein (α-Syn) into insoluble aggregates called Lewy pathology. The Line 61 α-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human α-Syn expression, and features of sporadic PD develop at 9–18 months of age. To accelerate the PD phenotypes, we injected sonicated human α-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-α-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-α-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45+ cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model. [ABSTRACT FROM AUTHOR]

The study aimed to investigate the combined effects of chlorpyrifos and cypermethrin combined on dopaminergic neurotoxicity, motor behaviours and level of selected inflammatory proteins in rats compared to either alone for delineating an interaction between these two pesticides. The rotarod and grip strength tests were employed to assess neurobehavioural changes. The striatal dopamine content and expression of tyrosine hydroxylase (TH), α-synuclein, cyclooxygenase-2 (COX-2), and tumour necrosis factor-α (TNF-α) proteins in the nigrostriatal tissue were measured. Chlorpyrifos impaired the neurobehavioural indexes, reduced the striatal dopamine level, augmented the level of α-synuclein, COX-2, and TNF-α and attenuated the expression of TH similar to but a little less than cypermethrin. Half the dose of both pesticides together produced additional neurotoxicity compared with the usual (highest employed) dose of either alone. The results showed that chlorpyrifos induced moderately less dopaminergic neurotoxicity than cypermethrin. In the combination, they produced a little higher toxicity than either pesticide alone. [ABSTRACT FROM AUTHOR]

Amyloids interact with plasma membranes. Extracellular amyloids cross the plasma membrane barrier. Internalized extracellular amyloids are reported to trigger amyloidogenesis of endogenous proteins in recipient cells. To what extent these extracellular and intracellular amyloids perturb the plasma membrane proteome is not investigated. Using α-synuclein as a model amyloid protein, we performed membrane shaving followed by mass spectrometry experiments to identify the conformational changes in cell surface proteins after extracellular amyloid challenge. We also performed membrane proteomics after the biogenesis of intracellular α-synuclein amyloids. Our results suggest that promiscuous interactions with extracellular amyloids stochastically alter the conformation of plasma membrane proteins. This affects the biological processes through the plasma membrane and results in loss of cell viability. Cells that survive the extracellular amyloid shock can grow normally and gradually develop intracellular amyloids which do not directly impact the plasma membrane proteome and associated biological processes. Thus, our results suggest that α-synuclein amyloids can damage the plasma membrane and related processes during cell-to-cell transfer and not during their intracellular biogenesis. [ABSTRACT FROM AUTHOR]

Among the proteins expressed most abundantly in erythrocytes is α-synuclein, and erythrocytes are emerging as key players in synucleinopathy-related alterations. Extracellular vesicles derived from α-synuclein-containing erythrocytes may cross the blood–brain barrier or enter the gastrointestinal tract and contribute to Parkinson's disease progression. Erythrocyte-based biomarkers, especially those linked to synucleinopathy pathology, could aid in differentiating Parkinson's disease from other movement disorders. Erythrocytes and erythrocyte-derived extracellular vesicles have unique biological characteristics, making them attractive targets for the development of therapeutic approaches for synucleinopathies and other disorders. Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are characterized by neuronal loss accompanied by α-synuclein (α-syn) accumulation in the brain. While research conventionally focused on brain pathology, there is growing interest in peripheral alterations. Erythrocytes, which are rich in α-syn, have emerged as a compelling site for synucleinopathies-related alterations. Erythrocyte-derived extracellular vesicles (EVs), containing pathological α-syn species, can traverse the blood–brain barrier (BBB) under certain conditions and the gastrointestinal tract, where α-syn and gut microbiota interact extensively. This review explores the accumulating evidence of erythrocyte involvement in synucleinopathies, as well as their potential in disease pathogenesis and diagnosis. Given their unique properties, erythrocytes and erythrocyte-derived EVs may also serve as an ideal therapeutic platform for treating synucleinopathies and beyond. [ABSTRACT FROM AUTHOR]

Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, are emerging as new scientific fields for understanding the pathology of human diseases, regenerative medicine, and drug discovery. In recent years, advanced technologies for cell culture and neuronal differentiation of human cells have provided stable and reproducible methods, contributing to the development of new cross-disciplinary scientific trends alongside various research technologies. Here, we introduce our recent research on brain region-specific neuronal differentiation and brain organoid induction from human pluripotent stem cells, as well as their application for disease modeling and regenerative medicine. Furthermore, we discuss the future direction and application of human pluripotent stem cell technology in advancing scientific discovery. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide; therefore, since its initial description, significant progress has been made, yet a mystery remains regarding its pathogenesis and elusive root cause. The widespread distribution of pathological α-synuclein (αSyn) aggregates throughout the body raises inquiries regarding the etiology, which has prompted several hypotheses, with the most prominent one being αSyn-associated proteinopathy. The identification of αSyn protein within Lewy bodies, coupled with genetic evidence linking αSyn locus duplication, triplication, as well as point mutations to familial Parkinson's disease, has underscored the significance of αSyn in initiating and propagating Lewy body pathology throughout the brain. In monogenic and sporadic PD, the presence of early inflammation and synaptic dysfunction leads to αSyn aggregation and neuronal death through mitochondrial, lysosomal, and endosomal functional impairment. However, much remains to be understood about αSyn pathogenesis, which is heavily grounded in biomarkers and treatment strategies. In this review, we provide emerging new evidence on the current knowledge about αSyn's pathophysiological impact on PD, and its presumable role as a specific disease biomarker or main target of disease-modifying therapies, highlighting that this understanding today offers the best potential of disease-modifying therapy in the near future. [ABSTRACT FROM AUTHOR]

Learning and memory mainly rely on correct synaptic function in the hippocampus and other brain regions. In Parkinsons disease, subtle cognitive deficits may even precede motor signs early in the disease. Hence, we set out to unravel the earliest hippocampal synaptic alterations associated with human α-synuclein overexpression prior to and soon after the appearance of cognitive deficits in a parkinsonism model. We bilaterally injected adeno-associated viral vectors encoding A53T-mutated human α-synuclein into the substantia nigra of rats, and evaluated them 1, 2, 4 and 16 weeks post-inoculation by immunohistochemistry and immunofluorescence to study degeneration and distribution of α-synuclein in the midbrain and hippocampus. The object location test was used to evaluate hippocampal-dependent memory. Sequential window acquisition of all theoretical mass spectrometry-based proteomics and fluorescence analysis of single-synapse long-term potentiation were used to study alterations to protein composition and plasticity in isolated hippocampal synapses. The effect of L-DOPA and pramipexole on long-term potentiation was also tested. Human α-synuclein was found within dopaminergic and glutamatergic neurons of the ventral tegmental area, and in dopaminergic, glutamatergic and GABAergic axon terminals in the hippocampus from 1 week post-inoculation, concomitant with mild dopaminergic degeneration in the ventral tegmental area. In the hippocampus, differential expression of proteins involved in synaptic vesicle cycling, neurotransmitter release and receptor trafficking, together with impaired long-term potentiation were the first events observed (1 week post-inoculation), preceding cognitive deficits (4 weeks post-inoculation). Later on, at 16 weeks post-inoculation, there was a deregulation of proteins involved in synaptic function, particularly those involved in the regulation of membrane potential, ion balance and receptor signalling. Hippocampal long-term potentiation was impaired before and soon after the onset of cognitive deficits, at 1 and 4 weeks post-inoculation, respectively. L-DOPA recovered hippocampal long-term potentiation more efficiently at 4 weeks post-inoculation than pramipexole, which partially rescued it at both time points. Overall, we found impaired synaptic plasticity and proteome dysregulation at hippocampal terminals to be the first events that contribute to the development of cognitive deficits in experimental parkinsonism. Our results not only point to dopaminergic but also to glutamatergic and GABAergic dysfunction, highlighting the relevance of the three neurotransmitter systems in the ventral tegmental area-hippocampus interaction from the earliest stages of parkinsonism. The proteins identified in the current work may constitute potential biomarkers of early synaptic damage in the hippocampus and hence, therapies targeting these could potentially restore early synaptic malfunction and consequently, cognitive deficits in Parkinsons disease.

Abstract To investigate physiological function of α-synuclein is important for understanding its pathophysiological mechanism in synucleinopathies including Parkinson’s disease. Employing knockout mice, we found that Snac/α-synuclein deletion induced aberrant projection of olfactory sensory neurons and hyposmia. We identified 9 axon guidance associated differentially expressed proteins using iTRAQ based Liquid Chromatograph Mass Spectrometer. NCK2 is most significantly down-regulated protein among them. We further found that either α-synuclein deletion or NCK2 deficiency induced Eph A4 inactivation. Re-expressing Snac/α-synuclein in its knockout neurons reversed the down-regulation of NCK2, as well as the inactivation of EphA4. Overexpression of Snac/α-synuclein in α-synuclein deleted mice reversed the down-regulation of NCK2 and pEphA4, and improved the olfactory impairment of mice. Correlation analysis showed that there is a significant correlation between the protein level of α-synuclein, NCK2, and pEphA4, respectively. Nonetheless, immunoprecipitation analysis showed that NCK2 was associated with both EphA4 and Rho A, suggesting that NCK2 as a scaffolding protein to modulate Eph A4/Rho A pathway. Moreover, Rho A activity was significantly lower in α-synuclein deficient mice. Thus, α-synuclein regulates olfactory neurons projection through NCK2 dependent EphA4/Rho A pathway. Malfunction of α-synuclein because of deletion may cause aberrant olfactory neurons projection. This extended our knowledge of α-synuclein functions, which may explain why olfaction is usually impaired in some synucleinopathies.

Sirtuins(SIRTs), a group of NAD+ dependent deacetylases, have attracted considerable attention in the field of neuro-degenerative diseases, especially Parkinson's disease (PD). They have critical impacts on cell survival and death through modulation of various biological processes, such as intracellular metabolism, stress response and DNA repair. In the pathogenesis of PD, Sirtuins play a crucial role and associated with pathophysiological processes such as mitochondrial function, oxidative stress, and neuronal apoptosis. Activation of Sirtuins alleviates dyskinesia and neuronal damage in animal models of PD and also regulates the aggregation and clearance of α-synuclein, a pathological feature of the disease. Therefore, the modulation of Sirtuins is a potential strategy for treating PD.

Abstract The Parkinson’s disease protein, alpha-synuclein (α-syn/SNCA), is highly expressed in neurons and melanomas. The goal of this study was to reveal the mechanism(s) of α-syn’s involvement in melanoma pathogenesis. To decipher the genes and pathways affected by α-syn, we conducted an RNA sequencing analysis of human SK-MEL-28 cells and several SK-MEL-28 SNCA-KO clones. We identified 1098 significantly up-regulated genes and 660 significantly down-regulated genes. Several of the upregulated genes are related to the immune system, i.e., the inflammatory response and the matrisome. We validated five upregulated genes (IL-1β, SAA1, IGFBP5, CXCL8, and CXCL10) by RT-qPCR and detected IGFBP5 and IL-1β in spent media of control and SNCA-KO cells. The levels of each of these secreted proteins were significantly higher in the spent media of the SNCA-KO clones than control cells. These secreted proteins quite likely activate the immune response against SNCA-KO cells. We suggest that, conversely, high levels of α-syn expression in melanoma cells helps the cells evade the immune system by inhibiting the secretion of these immune activating factors.