Pathogenesis Of Parkinson's Disease Research Articles

Genetically modified E. Coli secreting melanin (E.melanin) activates the astrocytic PSAP-GPR37L1 pathway and mitigates the pathogenesis of Parkinson’s disease

The characteristic neuropathology of Parkinson’s disease (PD) involves the abnormal accumulation of phosphorylated α-synuclein (αSyn), as well as a significant decrease in neuromelanin (NM) levels within dopamine neurons (DaNs). Unlike αSyn aggregates, the relationship between NM levels and PD pathogenesis is not well understood. In this study, we engineered an E. coli MG1655 strain to produce exosomes containing melanin (E.melanin), and investigated its potential neuroprotective effects on DaNs in the context of PD. By employing a combination of cell cultures, biochemical studies, single nuclear RNA sequencing (snRNA seq), and various in vivo validations, we found that administration of E.melanin effectively alleviated DaNs loss and improved motor behavior impairments observed in both pharmacological and transgenic PD mouse models. Mechanistically, snRNA seq data suggested that E.melanin activated the PSAP-GPR37L1 signaling pathway specifically within astrocytes, leading to a reduction in astrocytic engulfment of synapses. Notably, activation of the GPR37L1 receptor using Tx14(A) peptide successfully rescued motor defects as well as protected against DaNs degeneration in mice with PD. Overall, our findings provide novel insights into understanding the molecular mechanisms underlying melanin’s protective effects on DaNs in PD while offering potential strategies for manipulating and treating its pathophysiological progression.

Intersection of Sleep Disorders and Parkinson Disease: Unveiling the Bidirectional Relationship

AbstractBackgroundPatients with Parkinson's Disease (PD) frequently exhibit non‐motor symptoms, particularly sleep disturbances. Sleep disorders in PD patients are intricately linked to the pathogenesis and progression of PD itself, exacerbating neurodegenerative processes and worsening patient quality of life.ObjectivesThis review underscores the significance of sleep disorders in PD, highlighting their prevalence, impact on disease progression, and the bidirectional relationship between sleep disruption and neurodegeneration. It aims to enhance clinician awareness for better diagnosis and management of sleep‐related comorbidities in PD.MethodsA comprehensive literature search was conducted in PubMed and Scopus using key terms such as “sleep disorders”, “Parkinson's disease”, “REM sleep behavior disorder”, “restless legs syndrome”, “insomnia”, “obstructive sleep apnea”, “excessive daytime sleepiness”, “circadian rhythm disorders”, “sleep and neurodegeneration”.ResultsSleep disorders are prevalent in PD affecting up to 90% of patients. Conditions such as insomnia, REM sleep behavior disorder, restless legs syndrome, obstructive sleep apnea, excessive daytime sleepiness, and circadian rhythm disorders are commonly reported. These disorders are linked to multifactorial biological mechanisms and are associated with more severe disease phenotypes. Of note, several evidence shows that sleep abnormalities may contribute to neuroinflammation and neurodegeneration, further accelerating the disease course.ConclusionsSleep disturbances are critical non‐motor symptoms in PD. Early diagnosis and tailored management of sleep disorders are essential for improving clinical outcomes and potentially offering neuroprotective benefits.

Microbiome-based therapies for Parkinson’s disease

The human gut microbiome dysbiosis plays an important role in the pathogenesis of Parkinson’s disease (PD). The bidirectional relationship between the enteric nervous system (ENS) and central nervous system (CNS) under the mediation of the gut-brain axis control the gastrointestinal functioning. This review article discusses key mechanisms by which modifications in the composition and function of the gut microbiota (GM) influence PD progression and motor control loss. Increased intestinal permeability, chronic inflammation, oxidative stress, α-synuclein aggregation, and neurotransmitter imbalances are some key factors that govern gastrointestinal pathology and PD progression. The bacterial taxa of the gut associated with PD development are discussed with emphasis on the enteric nervous system (ENS), as well as the impact of gut bacteria on dopamine production and levodopa metabolism. The pathophysiology and course of the disease are associated with several inflammatory markers, including TNF-α, IL-1β, and IL-6. Emerging therapeutic strategies targeting the gut microbiome include probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation (FMT). The article explored how dietary changes may affect the gut microbiota (GM) and the ways that can affect Parkinson’s disease (PD), with a focus on nutrition-based, Mediterranean, and ketogenic diets. This comprehensive review synthesizes current evidence on the role of the gut microbiome in PD pathogenesis and explores its potential as a therapeutic target. Understanding these complex interactions may assist in the development of novel diagnostic tools and treatment options for this neurodegenerative disorder.

Insulin Resistance Is a Modifying Factor for Parkinson's Disease.

Parkinson's disease (PD) is the second most common, and the fastest-growing neurodegenerative disorder with unclear etiology in most cases. Therefore, the identification of non-genetic risk factors for PD pathology is crucial to develop effective preventative or therapeutic strategies. An increasing number of evidence suggests that central insulin resistance might have an essential role in PD pathology. Nevertheless, it is not clear whether insulin resistance arises from external factors/lifestyle, comorbidities such as type 2 diabetes or it can occur in a PD patient's brain independently from peripheral insulin resistance. We aimed to investigate insulin resistance and its role in GBA1mutation-associated PD pathogenesis and phenotype severity. Midbrain organoids, generated from induced pluripotent stem cells (iPSCs) of PD patients carrying the GBA1-N370S heterozygous mutation (GBA-PD) and healthy donors, were exposed to different insulin concentrations to modify insulin signaling function. Transcriptomics analysis was performed to explore insulin signaling gene expression patterns in GBA-PD and to find a potential target for GBA-PD-associated phenotype rescue. The insulin signaling pathway genes show dysregulation in GBA-PD. Particularly, we highlight that a knockdown of FOXO1 mitigates the loss of dopaminergic neurons and cellular death in GBA-PD. Additionally, our findings suggest a promising therapeutic potential of the anti-diabetic drug Pioglitazone in decreasing dopaminergic neuron loss associated with GBA-PD. Local insulin signaling dysfunction plays a substantial role in GBA-PD pathogenesis, exacerbating dopaminergic neuron death. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Understanding Parkinson disease in Spain: Genetic and clinical insights.

Parkinson disease (PD) is a complex and heterogeneous neurodegenerative disorder with a broad spectrum of clinical manifestations, determined by a complex interplay of environmental and genetic factors. This study aimed to investigate genetic variants associated with PD and assess their impact on the disease phenotype through genotype-phenotype correlations. We employed a targeted resequencing panel to analyze 27 genes linked to PD in a cohort of 1185 PD patients from southern Spain. Variants were categorized based on the American College of Medical Genetics and Genomics pathogenicity criteria. Demographic and clinical data were also collected. Among the patients analyzed, 13.5% carried potential disease-causing pathogenic or likely pathogenic variants in 12 different genes, indicating significant genetic heterogeneity. The most frequently affected genes were LRRK2, PRKN, and GBA1 (accounting for 72.1% of positive cases). Sex-specific differences were observed, with a higher proportion of female patients carrying LRRK2 variants. Differences in age at onset and clinical features were also observed among the different mutated genes. Notably, variants in genes associated with atypical parkinsonism presented distinct clinical presentations, highlighting the importance of genetic factors in the differential diagnosis. Our study provides valuable information on the genetic landscape of PD and its clinical manifestations. The observed genotype-phenotype correlations, along with sex-specific differences, emphasize the complexity of PD pathogenesis, underlining the importance of personalized approaches to PD diagnosis and treatment. Further investigations into genetic interactions and population-specific effects are warranted to enhance our understanding of PD etiology and improve patient care.

Brain single-cell transcriptomics highlights comorbidity-related cell type-specific changes of Parkinson’s disease with major depressive disorder after paraquat exposure

Paraquat (PQ), a commonly used herbicide, is a potent environmental neurotoxin associated with Parkinson’s disease (PD) and major depressive disorder (MDD). While the involvement of various brain cell types in the etiology of each disorder is well recognized, the specific cell subtypes implicated in the comorbidity of PD and MDD, especially under PQ neurotoxicity, remain poorly understood. In this study, we used single-cell RNA sequencing (scRNA-seq) to analyze brain tissues from mice with PQ-induced PD with MDD. By integrating genomic data with scRNA-seq profiles, we identified differences in cellular heterogeneity related to the pathogenesis of PD and MDD under PQ exposure. Our analysis of risk enrichment in genes with cell type-specific expression patterns revealed that astrocytes are predominantly linked to the comorbidity of PQ-induced PD and MDD. Furthermore, we identified a specific astrocyte subtype that plays a major role in the comorbidity-related changes observed in PQ-induced PD and MDD. This subtype appears to interact with and potentially transform into MDD-specific and PD-specific subtypes. Additionally, pathways related to chemical synaptic function and neuro-projection development were involved in all key stages of PD and MDD co-occurrence. We also identified RNF7 and MTCH2 as shared diagnostic hub genes for PD and MDD, which changed significantly in astrocytes following PQ exposure. These genes may serve as potential markers for astrocyte-specific prognostic diagnosis of PQ-induced PD with MDD. In summary, this study provides the first scRNA-seq profile of comorbidity in a PQ-exposed model. It highlights the heterogeneity of astrocytes in comorbidity and elucidates potential mechanisms underlying the co-occurrence of PD and MDD. These findings emphasize the need for further research into the pathogenesis of PD comorbid with MDD and offer novel insights into PQ neurotoxicity.

Hsa_Circ_0105596/FTO Inhibits Progression of Parkinson's disease by Sponging miR-187-3p and Regulating eEF2

Backgroud:Parkinson's disease (PD) characterized by inflammation and protein erroneous deposition, whose pathological mechanisms have not been elucidated. NcRNA plays important role in PD, especially when circRNA sponges miRNA, which leads to the breakdown of downstream regulation. The aim of this study is to investigate the dynamic changes between upregulated circRNA and downregulated miRNA during the pathogenesis of PD and their impact on downstream miRNA targets. MethodWe conducted bioinformatics on sequencing data of substantia nigra (SN) and striatum, and intersected differentially expressed genes (Degs) to determine core role of circFTO-miR-187-3p-EEF2 axes in the progression of PD. Firstly, therapeutic effect of knock-down circFTO in PD and its impact on EEF2 were determined in mouse, using immunohistochemistry, HE, Nissl, TUNEL staining and western blot (WB). Targeted binding relationship between circFTO, miR-187-3p, and EEF2 was determined through RNA binding protein immunoprecipitation assays (RIP) and dual luciferase reporter assay. The significance of gene in apoptosis was confirmed through flow cytometry, lentiviral transduction, quantitative real-time PCR, and WB. ResultCircFTO is upregulated and miR-187-3p is downregulated in SN of PD. EEF2 was the core of neural repair related modules in both SN and striatum using Weighted Correlation Network Analysis (WGCNA) and protein-protein interaction (PPI). The binding regulation relationship between circFTO-miR-187-3p-EEF2 was determined through structural analysis, RIP, and dual luciferase reporter assay. After knocking-down circFTO, animals showed alleviated symptoms, decreased levels of oxidative stress and EEF2. Upregulation of miR-187-3p or si-circFTO in SH-SY5Y cells can reduce cell apoptosis, EEF2, and oxidative stress. Moreover, individual interference with EEF2 can partially counteract the induction of 6-OHDA on apoptosis. ConclusionExcessive circFTO sponging miR-187-3p leads to the inability of miR-187-3p to effectively regulate expression of EEF2, resulting in the progression of PD. Moreover, interference with circFTO can effectively reduce brain inflammation and oxidative stress.

The Common Denominators of Parkinson's Disease Pathogenesis and Methamphetamine Abuse.

The pervasiveness and mortality associated with methamphetamine abuse have doubled during the past decade, suggesting a possible worldwide substance use crisis. Epitomizing the pathophysiology and toxicology of methamphetamine abuse proclaims severe signs and symptoms of neurotoxic and neurobehavioral manifestations in both humans and animals. Most importantly, chronic use of this drug enhances the probability of developing neurodegenerative diseases manifolds. Parkinson's disease is one such neurological disorder, which significantly and evidently not only shares a number of toxic pathogenic mechanisms induced by methamphetamine exposure but is also interlinked both structurally and genetically. Methamphetamine-induced neurodegeneration involves altered dopamine homeostasis that promotes the aggregation of α-synuclein protofibrils in the dopaminergic neurons and drives these neurons to make them more vulnerable to degeneration, as recognized in Parkinson's disease. Moreover, the pathologic mechanisms such as mitochondrial dysfunction, oxidative stress, neuroinflammation and decreased neurogenesis detected in methamphetamine abusers dramatically resemble to what is observed in Parkinson's disease cases. Therefore, the present review comprehensively cumulates a holistic illustration of various genetic and molecular mechanisms putting across the notion of how methamphetamine administration and intoxication might lead to Parkinson's disease-like pathology and Parkinsonism.

Parkinson’s disease models and death signaling: what do we know until now?

Parkinson’s disease (PD) is the second neurodegenerative disorder most prevalent in the world, characterized by the loss of dopaminergic neurons in the Substantia Nigra (SN). It is well known for its motor and non-motor symptoms including bradykinesia, resting tremor, psychiatric, cardiorespiratory, and other dysfunctions. Pathological apoptosis contributes to a wide variety of diseases including PD. Various insults and/or cellular phenotypes have been shown to trigger distinct signaling events leading to cell death in neurons affected by PD. The intrinsic or mitochondrial pathway, inflammatory or oxidative stress-induced extrinsic pathways are the main events associated with apoptosis in PD-related neuronal loss. Although SN is the main brain area studied so far, other brain nuclei are also affected by the disease leading to non-classical motor symptoms as well as non-motor symptoms. Among these, the respiratory symptoms are often overlooked, yet they can cause discomfort and may contribute to patients shortened lifespan after disease diagnosis. While animal and in vitro models are frequently used to investigate the mechanisms involved in the pathogenesis of PD in both the SN and other brain regions, these models provide only a limited understanding of the disease’s actual progression. This review offers a comprehensive overview of some of the most studied forms of cell death, including recent research on potential treatment targets for these pathways. It highlights key findings and milestones in the field, shedding light on the potential role of understanding cell death in the prevention and treatment of the PD. Therefore, unraveling the connection between these pathways and the notable pathological mechanisms observed during PD progression could enhance our comprehension of the disease’s origin and provide valuable insights into potential molecular targets for the developing therapeutic interventions.

Convergence of Neuroinflammation, Microbiota, and Parkinson’s Disease: Therapeutic Insights and Prospects

Parkinson’s disease (PD) is a complex neurodegenerative disorder. Recent evidence reveals connections between neuroinflammatory processes and intestinal microbiota alterations in the progression of this pathology. This comprehensive review explores the intricate relationships between them, highlighting their combined impact on PD. Neuroinflammation, characterized by immune activation in the central nervous system, is increasingly acknowledged as a critical factor in the development of PD. Concurrently, alterations in the gut microbiota composition have been linked to PD, suggesting a potential modulatory role in disease progression. Thus, bidirectional communication along the gut–brain axis has become pivotal in comprehending the pathogenesis of PD. Furthermore, we explore emerging therapeutic strategies that target these interconnected pathways, providing insights into potential avenues for PD treatment. The elucidation of these intricate relationships establishes a promising foundation for innovative therapeutic strategies aimed at altering disease progression and improving the quality of life for individuals affected by PD.

Gut Microbiota and Parkinson’s disease - a prospective analysis of the FINRISK 2002 Study

Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder with mainly unknown etiology. Constipation is a common symptom, and changes in gut microbiota may play role in PD pathogenesis. Previous studies exploring microbial associations to PD have been mostly cross-sectional, and the role of microorganisms in PD etiology remains unclear. Thus, we examined the association between microbiota features and incident PD in a prospective cohort design. Methods In the FINRISK 2002 Study, 7231 participants gave a stool sample that underwent shotgun metagenomic sequencing. Participants with missing stool sample, incomplete covariate data, pregnancy, antibiotic use, and prevalent cases were excluded (final n = 5562). Cox regression models, adjusted for age, sex, education, smoking, coffee consumption, diabetes, cardiovascular events, and constipation, were used to assess associations between incident PD and microbiota features, ie. alpha diversity (the number of different species present in a sample), beta diversity (the differences in microbial composition between individuals), and abundance of 381 core taxa (compositional detection rate of at least 0.1% and a prevalence of 1%). 120 incident cases of PD, identified through register linkage, occurred during a median follow-up of 17.8 years. Results In the multivariate models, PD incidence was not associated with the Shannon index, a measure on alpha diversity, (p-value 0.81), or with the ten first principal component axes in beta diversity analysis (p-values ranging between 0.49-0.91). In permutational analysis, PD did not explain differences in the composition of the gut microbiota (R2 <0.001, p-value 0.46)). None of the core species were associated with PD incidence (all FDR-corrected p-values > 0.05). Conclusions This prospective study showed no support for an association between gut microbiota features and incident PD. Key messages • Previous findings associating gut microbiota with PD may be due to the cross-sectional design, ie. PD affecting the gut microbiota. • Suggestions to screen gut bacteria to identify people at high risk of Parkinson’s disease are vastly premature as the scientific evidence is inconclusive.

Liquid-liquid phase separation and conformational strains of α-Synuclein: implications for Parkinson's disease pathogenesis.

Parkinson's disease (PD) and other synucleinopathies are characterized by the aggregation and deposition of alpha-synuclein (α-syn) in brain cells, forming insoluble inclusions such as Lewy bodies (LBs) and Lewy neurites (LNs). The aggregation of α-syn is a complex process involving the structural conversion from its native random coil to well-defined secondary structures rich in β-sheets, forming amyloid-like fibrils. Evidence suggests that intermediate species of α-syn aggregates formed during this conversion are responsible for cell death. However, the molecular events involved in α-syn aggregation and its relationship with disease onset and progression remain not fully elucidated. Additionally, the clinical and pathological heterogeneity observed in various synucleinopathies has been highlighted. Liquid-liquid phase separation (LLPS) and condensate formation have been proposed as alternative mechanisms that could underpin α-syn pathology and contribute to the heterogeneity seen in synucleinopathies. This review focuses on the role of the cellular environment in α-syn conformational rearrangement, which may lead to pathology and the existence of different α-syn conformational strains with varying toxicity patterns. The discussion will include cellular stress, abnormal LLPS formation, and the potential role of LLPS in α-syn pathology.

Role of Peroxynitrite in the Pathogenesis of Parkinson's Disease and Its Fluorescence Imaging-Based Detection.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting the lives of millions of people worldwide. Although the mechanism underlying PD pathogenesis is largely undefined, increasing evidence indicates that oxidative and nitrosative stresses play a crucial role in PD occurrence and development. Among them, the role of oxidative stress has been widely acknowledged, but there is relatively less attention given to nitrosative stress, which is mainly derived from peroxynitrite. In the present review, after briefly introducing the background of PD, we discuss the physiopathological function of peroxynitrite and especially highlight how overloaded peroxynitrite is involved in PD pathogenesis. Then, we summarize the currently reported fluorescence imaging-based peroxynitrite detection probes. Moreover, we specifically emphasize the probes that have been applied in PD research. Finally, we propose perspectives on how to develop a more applicable peroxynitrite probe and leverage it for PD theranostics. Conclusively, the present review broadens the knowledge on the pathological role of peroxynitrite in the context of PD and sheds light on how to develop and utilize fluorescence imaging-based strategies for peroxynitrite detection.

Deficiency of parkin causes neurodegeneration and accumulation of pathological α-synuclein in monkey models.

Parkinson's disease (PD) is characterized by age-dependent neurodegeneration and the accumulation of toxic phosphorylated α-synuclein (pS129-α-syn). The mechanisms underlying these crucial pathological changes remain unclear. Mutations in parkin RBR E3 ubiquitin protein ligase (PARK2), the gene encoding parkin that is phosphorylated by PTEN-induced putative kinase 1 (PINK1) to participate in mitophagy, cause early onset PD. However, current parkin-KO mouse and pig models do not exhibit neurodegeneration. In the current study, we utilized CRISPR/Cas9 technology to establish parkin-deficient monkey models at different ages. We found that parkin deficiency leads to substantia nigra neurodegeneration in adult monkey brains and that parkin phosphorylation decreases with aging, primarily due to increased insolubility of parkin. Phosphorylated parkin is important for neuroprotection and the reduction of pS129-α-syn. Consistently, overexpression of WT parkin, but not a mutant form that cannot be phosphorylated by PINK1, reduced the accumulation of pS129-α-syn. These findings identify parkin phosphorylation as a key factor in PD pathogenesis and suggest it as a promising target for therapeutic interventions.

Bile Acids as Modulators of α-Synuclein Aggregation: Implications for Parkinson's Therapy.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the aggregation of α-synuclein into toxic amyloid fibrils. Recent research suggests that bile acids altered in PD may influence their aggregation. This study investigates the effects of lithocholic acid (LCA) and deoxycholic acid (DCA) on α-synuclein aggregation and toxicity. LCA significantly accelerates aggregation, reducing the lag phase by 75%, while DCA has a milder impact, decreasing the lag phase by 30%. Binding studies show that LCA interacts with the NAC region and DCA with the N-terminal region of α-synuclein. Aggregation assays and electrophoresis reveal that LCA promotes the formation of toxic, SDS-resistant oligomers more effectively than DCA. Cytotoxicity assays confirm a lower cell viability in LCA-treated samples. Additionally, combined LCA and DCA treatment results in enhanced aggregation and toxicity, indicating a synergistic effect. These findings highlight the role of bile acids in α-synuclein aggregation and PD pathogenesis, suggesting that targeting bile acid metabolism could be a therapeutic strategy for PD.

An immunoassay for the quantification of phosphorylated α-synuclein at serine 129 in human cerebrospinal fluid.

The link between alpha Synuclein (α-Syn) phosphorylation and Parkinson's disease pathogenesis has not been fully elucidated, in part due to analytical methods with finite specificity and sensitivity, resulting in conflicting data on pathophysiological levels of the protein.One factor hindering the assessment of the role of pSer129 α-Syn is the lack of a fit for purpose assay. Antibodies were assessed for quantification of pSer129 α-Syn, resulting in a sensitive and specific assay suitable for use in Parkinson's disease and control CSF, with no significant difference found between the two populations. Total α-Syn was measured using a commercial kit, demonstrating a positive correlation between total and pSer129 α-Syn.This adds to available methods for pSer129 α-Syn in support of α-synucleinopathy research.

A comprehensive review of natural compounds and their structure-activity relationship in Parkinson's disease: exploring potential mechanisms.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopamine-producing cells in the Substantia nigra region of the brain. Complementary and alternative medicine approaches have been utilized as adjuncts to conventional therapies for managing the symptoms and progression of PD. Naturalcompounds have gained attention for their potential neuroprotective effects and ability to target various pathways involved in the pathogenesis of PD. This comprehensive review aims to provide an in-depth analysis of the molecular targets and mechanisms of natural compounds in various experimental models of PD. This review will also explore the structure-activity relationship (SAR) of these compounds and assess the clinical studies investigating the impact of these natural compounds on individuals with PD. The insights shared in this review have the potential to pave the way for the development of innovative therapeutic strategies and interventions for PD.

Pink1/Parkin deficiency alters circulating lymphocyte populations and increases platelet-T cell aggregates in rats

Parkinson’s disease (PD) is the most common progressive neurodegenerative movement disorder and results from the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Pink1 and Parkin are proteins that function together in mitochondrial quality control, and when they carry loss-of-function mutations lead to familial forms of PD. While much research has focused on central nervous system alterations in PD, peripheral contributions to PD pathogenesis are increasingly appreciated. We report Pink1/Parkin regulate glycolytic and mitochondrial oxidative metabolism in peripheral blood mononuclear cells (PBMCs) from rats. Pink1/Parkin deficiency induces changes in the circulating lymphocyte populations, namely increased CD4 + T cells and decreased CD8 + T cells and B cells. Loss of Pink1/Parkin leads to elevated platelet counts in the blood and increased platelet-T cell aggregation. Platelet-lymphocyte aggregates are associated with increased thrombosis risk suggesting targeting the Pink1/Parkin pathway in the periphery might have therapeutic potential.

Natural variation in age-related dopamine neuron degeneration is glutathione dependent and linked to life span

Aging is the biggest risk factor for Parkinson's disease (PD), suggesting that age-related changes in the brain promote dopamine neuron vulnerability. It is unclear, however, whether aging alone is sufficient to cause significant dopamine neuron loss, and if so, how this intersects with PD-related neurodegeneration. Here, through examining a large collection of naturally varying Drosophila strains, we find a strong relationship between life span and age-related dopamine neuron loss. Strains with naturally short-lived animals exhibit a loss of dopamine neurons without generalized neurodegeneration, while animals from long-lived strains retain dopamine neurons across age. Metabolomic profiling reveals lower glutathione levels in short-lived strains which is associated with elevated levels of reactive oxygen species (ROS), sensitivity to oxidative stress, and vulnerability to silencing the familial PD gene parkin. Strikingly, boosting neuronal glutathione levels via glutamate-cysteine ligase (Gcl) overexpression is sufficient to normalize ROS levels, extend life span, and block dopamine neurons loss in short-lived backgrounds, demonstrating that glutathione deficiencies are central to neurodegenerative phenotypes associated with short longevity. These findings may be relevant to human PD pathogenesis, where glutathione depletion is reported to occur in the idiopathic PD patient brain through unknown mechanisms. Building on this, we find reduced expression of the Gcl catalytic subunit in both Drosophila strains vulnerable to age-related dopamine neuron loss and in the human brain from familial PD patients harboring the common LRRK2 G2019S mutation. Our study across Drosophila and human PD systems suggests that glutathione synthesis and levels play a conserved role in regulating age-related dopamine neuron health.

Generation of an induced pluripotent stem cell line (HMSCATi004-A) from an early onset Parkinson’s disease patient with PRKN gene mutation

Parkin (PRKN) is recognized as causative gene in early-onset Parkinson’s disease (PD). Induced pluripotent stem cells (iPSCs) were derived from a 29-year-old PD patient carrying a heterozygous c.823C > T (p.R275W) variant and an exon 2–4 deletion in PRKN. The Generated iPSCs maintain a normal karyotype, express pluripotency markers, and retain the ability to differentiate into the three germ layers. This iPSC line serves as a valuable cellular model for investigating the pathogenesis of early-onset PD and development of potential therapeutic interventions.