Risk Factor For Parkinson's Disease Research Articles

High-fat diet exacerbates 1-Bromopropane-induced loss of dopaminergic neurons in the substantia nigra of mice through mitochondrial damage associated necroptotic pathway

In recent years, accumulating evidence supports that occupational exposure to solvents is associated with an increased incidence of Parkinson's disease (PD) among workers. The neurotoxic effects of 1-bromopropane (1-BP), a widely used new-type solvent, are well-established, yet data on its relationship with the etiology of PD remain limited. Simultaneously, high-fat consumption in modern society is recognized as a significant risk factor for PD. However, whether there is a synergistic effect between a high-fat diet and 1-BP exposure remains unclear. In this study, adult C57BL/6 mice were fed either a chow or a high-fat diet for 18 weeks prior to 12-week 1-BP treatment. Subsequent neurobehavioral and neuropathological examinations were conducted to assess the effects of 1-BP exposure on parkinsonian pathology. The results demonstrated that 1-BP exposure produced obvious neurobehavioral abnormalities and dopaminergic degeneration in the nigral region of mice. Importantly, a high-fat diet further exacerbated the impact of 1-BP on motor and cognitive abnormalities in mice. Mechanistic investigation revealed that mitochondrial damage and mtDNA release induced by 1-BP and high-fat diet activate NLRP3 and cGAS-STING pathway- mediated neuroinflammatory response, and ultimately lead to necroptosis of dopaminergic neurons. In summary, our study unveils a potential link between chronic 1-BP exposure and PD-like pathology with motor and no-motor defects in experimental animals, and long-term high-fat diet can further promote 1-BP neurotoxicity, which underscores the pivotal role of environmental factors in the etiology of PD.

Biomarkers of Physical and Mental Health for Prediction of Parkinson's Disease: A Population-Based Study from 15 European Countries

Early diagnosis of Parkinson's disease (PD) is critical for optimal treatment. However, the predictive potential of physical and mental health in PD is poorly characterized. We evaluated the potential of multiple demographic, physical, and mental factors in predicting the future onset of PD in older adults aged 50 years or older from 15 European countries. Individual study participants were followed over four waves of the Survey of Health, Ageing, and Retirement in Europe (SHARE) from 2013-2020. Of 57,980 study participants, 442 developed PD during the study period. We identified male sex and advancing age from the sixth decade of life onward as significant predictors of future PD. Among physical factors, a low handgrip strength (HGS; men <27 kg, women <16 kg), being bothered by frailty, and recent falls were significantly associated with future PD. Among mental factors, a higher depression (Euro-D depression score >6) emerged as an independent predictor of future PD. Finally, the presence of hypertension or Alzheimer's disease (AD) increases the risk of future PD. Altogether, male sex, advancing age, low HGS, frailty, depression, hypertension, and AD were identified as critical risk factors for future PD. Our results may be useful in the early identification and treatment of populations at risk for PD.

Human α-synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing.

Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague-Dawley rats received a unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration in SH-SY5Y cells. Furthermore, experiments in SH-SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of αSyn-induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing-related increases in αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.

Regulatory SVA retrotransposons and classical HLA genotyped-transcripts associated with Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative and polygenic disorder characterised by the progressive loss of neural dopamine and onset of movement disorders. We previously described eight SINE-VNTR-Alu (SVA) retrotransposon-insertion-polymorphisms (RIPs) located and expressed within the Human Leucocyte Antigen (HLA) genomic region of chromosome 6 that modulate the differential co-expression of 71 different genes including the HLA classical class I and class II genes in a Parkinson's Progression Markers Initiative (PPMI) cohort. In the present study, we (1) reanalysed the PPMI genomic and transcriptomic sequencing data obtained from whole blood of 1521 individuals (867 cases and 654 controls) to infer the genotypes of the transcripts expressed by eight classical HLA class I and class II genes as well as DRA and the DRB3/4/5 haplotypes, and (2) examined the statistical differences between three different PD subgroups (cases) and healthy controls (HC) for the HLA and SVA transcribed genotypes and inferred haplotypes. Significant differences for 57 expressed HLA alleles (21 HLA class I and 36 HLA class II alleles) up to the three-field resolution and four of eight expressed SVA were detected at p<0.05 by the Fisher's exact test within one or other of three different PD subgroups (750 individuals with PD, 57 prodromes, 60 individuals who had scans without evidence of dopamine deficits [SWEDD]), when compared against a group of 654 HCs within the PPMI cohort and when not corrected by the Bonferroni test for multiple comparisons. Fourteen of 20 significant alleles were unique to the PD-HC comparison, whereas 31 of the 57 alleles overlapped between two or more different subgroup comparisons. Only the expressed HLA-DRA*01:01:01 and -DQA1*03:01:01 protective alleles (PD v HC), the -DQA1*03:03:01 risk (HC v Prodrome) or protective allele (PD v Prodrome), the -DRA*01:01:02 and -DRB4*01:03:02 risk alleles (SWEDD v HC), and the NR_SVA_381 present genotype (PD v HC) at a 5% homozygous insertion frequency near HLA-DPA1, were significant (Pc<0.1) after Bonferroni corrections. The homologous NR_SVA_381 insertion significantly decreased the transcription levels of HLA-DPA1 and HLA-DPB1 in the PPMI cohort and its presence as a homozygous genotype is a risk factor (Pc=0.012) for PD. The most frequent NR_SVA_381 insertion haplotype in the PPMI cohort was NR_SVA_381/DPA1*02/DPB1*01 (3.7%). Although HLA C*07/B*07/DRB5*01/DRB1*15/DQB1*06 was the most frequent HLA 5-loci phased-haplotype (n, 76) in the PPMI cohort, the NR_SVA_381 insertion was present in only six of them (8%). These data suggest that expressed SVA and HLA gene alleles in circulating white blood cells are coordinated differentially in the regulation of immune responses and the long-term onset and progression of PD, the mechanisms of which have yet to be elucidated.

The Interplay of Mitochondrial Bioenergetics and Dopamine Agonists as an Effective Disease-Modifying Therapy for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurological ailment with a slower rate of advancement that is more common in older adults. The biggest risk factor for PD is getting older, and those over 60 have an exponentially higher incidence of this condition. The failure of the mitochondrial electron chain, changes in the dynamics of the mitochondria, and abnormalities in calcium and ion homeostasis are all symptoms of Parkinson's disease (PD). Increased mitochondrial reactive oxygen species (mROS) and an energy deficit are linked to these alterations. Levodopa (L-DOPA) is a medication that is typically used to treat most PD patients, but because of its negative effects, additional medications have been created utilizing L-DOPA as the parent molecule. Ergot and non-ergot derivatives make up most PD medications. PD is successfully managed with the use of dopamine agonists (DA). To get around the motor issues produced by L-DOPA, these dopamine derivatives can directly excite DA receptors in the postsynaptic membrane. In the past 10years, two non-ergoline DA with strong binding properties for the dopamine D2 receptor (D2R) and a preference for the dopamine D3 receptor (D3R) subtype, ropinirole, and pramipexole (PPx) have been developed for the treatment of PD. This review covers the most recent research on the efficacy and safety of non-ergot drugs like ropinirole and PPx as supplementary therapy to DOPA for the treatment of PD.

Dysfunction of synaptic endocytic trafficking in Parkinson's disease.

Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum. The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive. Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease. Notably, several of these genes are linked to the synaptic vesicle recycling process, particularly the clathrin-mediated endocytosis pathway. This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease, followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a "dying back" mechanism. Recently, several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized. These models faithfully recapitulate certain Parkinson's disease-like features at the animal, circuit, and cellular levels, and exhibit defects in synaptic membrane trafficking, further supporting the findings from human genetics and clinical studies. In this review, we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins: auxilin (DNAJC6/PARK19) and synaptojanin 1 (SYNJ1/PARK20). The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect. Subsequently, we will delve into the involvement of several clathrin-mediated endocytosis-related proteins (GAK, endophilin A1, SAC2/INPP5F, synaptotagmin-11), identified as Parkinson's disease risk factors through genome-wide association studies, in Parkinson's disease pathogenesis. We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins (alpha-synuclein (PARK1/4), Parkin (PARK2), and LRRK2 (PARK8)) in synaptic endocytic trafficking. Additionally, we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways, particularly autophagy. Given that synaptic dysfunction is considered as an early event in Parkinson's disease, a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel targets for early diagnosis and the development of interventional therapies for Parkinson's disease. Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson's disease.

Lysosomal storage, impaired autophagy and innate immunity in Gaucher and Parkinson's diseases: insights for drug discovery.

Impairment of autophagic-lysosomal pathways is increasingly being implicated in Parkinson's disease (PD). GBA1 mutations cause the lysosomal storage disorder Gaucher disease (GD) and are the commonest known genetic risk factor for PD. GBA1 mutations have been shown to cause autophagic-lysosomal impairment. Defective autophagic degradation of unwanted cellular constituents is associated with several pathologies, including loss of normal protein homeostasis, particularly of α-synuclein, and innate immune dysfunction. The latter is observed both peripherally and centrally in PD and GD. Here, we will discuss the mechanistic links between autophagy and immune dysregulation, and the possible role of these pathologies in communication between the gut and brain in these disorders. Recent work in a fly model of neuronopathic GD (nGD) revealed intestinal autophagic defects leading to gastrointestinal dysfunction and immune activation. Rapamycin treatment partially reversed the autophagic block and reduced immune activity, in association with increased survival and improved locomotor performance. Alterations in the gut microbiome are a critical driver of neuroinflammation, and studies have revealed that eradication of the microbiome in nGD fly and mouse models of PD ameliorate brain inflammation. Following these observations, lysosomal-autophagic pathways, innate immune signalling and microbiome dysbiosis are discussed as potential therapeutic targets in PD and GD. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

The Molecular Impact of Glucosylceramidase Beta 1 (Gba1) in Parkinson's Disease: a New Genetic State of the Art.

Parkinson's disease (PD) is a neurodegenerative disorder affecting 2-3% of those aged over 65, characterized by motor symptoms like slow movement, tremors, and muscle rigidity, along with non-motor symptoms such as anxiety and dementia. Lewy bodies, clumps of misfolded proteins, contribute to neuron loss in PD. Mutations in the GBA1 gene are considered the primary genetic risk factor of PD. GBA1 mutations result in decreased activity of the lysosomal enzyme glucocerebrosidase (GCase) resulting in α-synuclein accumulation. We know that α-synuclein aggregation, lysosomal dysfunction, and endoplasmic reticulum disturbance are recognized factors to PD susceptibility; however, the molecular mechanisms connecting GBA1 gene mutations to increased PD risk remain partly unknown. Thus, in this narrative review conducted according to a systematic review method, we aimed to present the main contributions arising from the molecular impact of the GBA1 gene to the pathogenesis of PD providing new insights into potential impacts for advances in the clinical care of people with PD, a neurological disorder that has contributed to the substantial increase in the global burden of disease accentuated by the aging population. In summary, this narrative review highlights the multifaceted impact of GBA1 mutations in PD, exploring their role in clinical manifestations, genetic predispositions, and molecular mechanisms. The review emphasizes the importance of GBA1 mutations in both motor and non-motor symptoms of PD, suggesting broader therapeutic and management strategies. It also discusses the potential of CRISPR/Cas9 technology in advancing PD treatment and the need for future research to integrate these diverse aspects for improved diagnostics and therapies.

Parkinson's Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges.

The core pathological event in Parkinson's disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca2+ oscillations in the absence of the Ca2+-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca2+ oscillations, and (3) providing bioenergetic support.

Exploring the causal relationship between B lymphocytes and Parkinson’s disease: a bidirectional, two-sample Mendelian randomization study

Parkinson’s disease (PD) is a neurodegenerative disorder with extensive involvement of motor symptoms, imposing a heavy economic burden on patients and society. B lymphocytes, a group of immune cells associated with humoral immunity, have been shown to be involved in the pathogenesis of PD. However, the causal relationship and potential pathogenic effects of B cell in PD remain unclear. Based on the three core hypotheses of the Mendelian randomization (MR) study, we explored causal associations between 190 B-cell immunological traits and 482,730 European individuals (Ncase = 33,674, Ncontrol = 449,056) from genome wide association studies by means of the two-sample bidirectional MR method. The inverse‑variance weighted method was selected as the main approach when conducting MR analysis. Finally, the results were verified by the heterogeneity and horizontal pleiotropy analyses. Five B-cell immunological phenotypes were nominally associated with PD at the significance threshold of P < 0.05. Concretely, IgD + CD38− B cell %lymphocyte (OR 1.052, 95% CI 1.001–1.106, P = 0.046), CD20 on IgD− CD24− B cell (OR 1.060, 95% CI 1.005–1.117, P = 0.032), CD38 on IgD+ CD24− B cell (OR 1.113, 95% CI 1.028–1.206, P = 0.009), and BAFF-R on CD20− B cell (OR 1.093, 95% CI 1.010–1.184, P = 0.027) were identified as risk factors for PD. Instead, CD38 on Plasma Blast-Plasma Cell (OR 0.894, 95% CI 0.802–0.996, P = 0.043) was proved to be protective. However, there is no statistically significant correlation between B cell and PD after Bonferroni correction. The results of reverse MR were negative, avoiding the reverse causal effects. Eventually, the association results were identified as stable across several sensitivity analyses. Briefly, our study might demonstrate the key factor of B cells in PD. Further studies are warranted to clarify the associations for early identification and immunotherapeutic development in PD patients.

Animal Approaches to Studying Risk Factors for Parkinson's Disease: A Narrative Review.

Despite recent efforts to search for biomarkers for the pre-symptomatic diagnosis of Parkinson's disease (PD), the presence of risk factors, prodromal signs, and family history still support the classification of individuals at risk for this disease. Human epidemiological studies are useful in this search but fail to provide causality. The study of well-known risk factors for PD in animal models can help elucidate mechanisms related to the disease's etiology and contribute to future prevention or treatment approaches. This narrative review aims to discuss animal studies that investigated four of the main risk factors and/or prodromal signs related to PD: advanced age, male sex, sleep alterations, and depression. Different databases were used to search the studies, which were included based on their relevance to the topic. Although still in a reduced number, such studies are of great relevance in the search for evidence that leads to a possible early diagnosis and improvements in methods of prevention and treatment.

Vitamin D Receptor Polymorphisms in a Spanish Cohort of Parkinson's Disease Patients.

Background: Vitamin D receptor (VDR) is a nuclear hormone receptor widely expressed in the substantia nigra. Its association with an increased risk of Parkinson's disease (PD) is based on vitamin D deficiency and/or different polymorphisms in its gene receptor. This fact has been demonstrated by several case-control studies. Materials and Methods: Consequently, we investigated the association between VDR ApaI, BsmI, FokI, and TaqI gene polymorphisms and PD in a Spanish cohort that included 54 cases and 17 healthy controls. The detection of single nucleotide polymorphisms (SNPs) was performed using a polymerase chain reaction-restriction fragment length polymorphism. Results: Our data indicate that the SNPs were not associated with the age of onset of PD, nor with the occurrence of motor symptoms. However, only BsmI polymorphism was significantly associated with PD in this Spanish cohort. In fact, BsmI genotype was five times higher among PD patients than among controls, and the A allele was considered as a genetic risk for PD. Additionally, the combination of FokI and BsmI polymorphisms was significantly associated with PD and could represent a risk factor. Conclusion: We conclude that ApaI, TaqI, and FokI polymorphisms were not associated with PD, but BsmI could be a risk factor for PD in this randomized population.

The SATB1-MIR22-GBA axis mediates glucocerebroside accumulation inducing a cellular senescence-like phenotype in dopaminergic neurons.

Idiopathic Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, which is associated with neuroinflammation and reactive gliosis. The underlying cause of PD and the concurrent neuroinflammation are not well understood. In this study, we utilize human and murine neuronal lines, stem cell-derived dopaminergic neurons, and mice to demonstrate that three previously identified genetic risk factors for PD, namely SATB1, MIR22HG, and GBA, are components of a single gene regulatory pathway. Our findings indicate that dysregulation of this pathway leads to the upregulation of glucocerebrosides (GluCer), which triggers a cellular senescence-like phenotype in dopaminergic neurons. Specifically, we discovered that downregulation of the transcriptional repressor SATB1 results in the derepression of the microRNA miR-22-3p, leading to decreased GBA expression and subsequent accumulation of GluCer. Furthermore, our results demonstrate that an increase in GluCer alone is sufficient to impair lysosomal and mitochondrial function, thereby inducing cellular senescence. Dysregulation of the SATB1-MIR22-GBA pathway, observed in both PD patients and normal aging, leads to lysosomal and mitochondrial dysfunction due to the GluCer accumulation, ultimately resulting in a cellular senescence-like phenotype in dopaminergic neurons. Therefore, our study highlights a novel pathway involving three genetic risk factors for PD and provides a potential mechanism for the senescence-induced neuroinflammation and reactive gliosis observed in both PD and normal aging.

Assessing the impact of novel risk loci on Alzheimer's and Parkinson's diseases in a Chinese Han cohort.

Overwhelming evidence points to that genetic factors contributing to the development of Alzheimer's disease (AD) and Parkinson's disease (PD). Genome-Wide Association Study (GWAS) has come a long way in the last decade. So far, a large number of GWAS studies have been published on neurological diseases and many other diseases, providing us with a wealth of genetic information and unique biological insights. Genomic DNA was extracted from both patients' and controls' peripheral blood samples utilizing the Blood Genome Extraction Kit. Single nucleotide polymorphisms (SNPs) were genotyped employing the enhanced multiple ligase detection reaction (iMLDR) technology. A case-control study was conducted, involving 211 AD patients, 508 PD patients (including 117 with dementia), and 412 healthy individuals. Age and sex stratification analysis revealed that rs871269/TNIP1 was associated with LOAD (p = 0.035), and rs5011436/TMEM106B was associated with AD in males (p = 0.044) in the genotype model. In the allele model, rs871269/TNIP1 was found to be associated with PD in the Chinese Han population (p = 0.0035, OR 0.741, 95% CI 0.559-0.983), and rs708382/GRN was identified as a risk factor for Parkinson's disease dementia (PDD) in the Chinese Han population (p = 0.004, odds ratio (OR) 0.354, 95% confidence interval (CI) 0.171-0.733). However, no significant associations with AD or PD were observed for the remaining four loci (rs113020870/AGRN, rs6891966/HAVCR2, rs2452170/NTN5, rs1761461/LILRB2) in terms of allele or genotype frequencies. This study identifies rs871269/TNIP1 as a potential risk factor for both LOAD and PD, rs708382/GRN as a risk factor for PDD, and rs5011436/TMEM106B as associated with AD in males when stratified by age.

Dopaminergic neuron loss in mice due to increased levels of wild-type human α-Synuclein only takes place under conditions of accelerated aging

Understanding the intricate pathogenic mechanisms behind Parkinson's disease (PD) and its multifactorial nature presents a significant challenge in disease modeling. To address this, we explore genetic models that better capture the disease's complexity. Given that aging is the primary risk factor for PD, this study investigates the impact of aging in conjunction with overexpression of wild-type human α-synuclein (α-Syn) in the dopaminergic system. This is achieved by introducing a novel transgenic mouse strain overexpressing α-Syn under the TH-promoter within the senescence-accelerated SAMP8 (P8) genetic background. Behavioral assessments, conducted at both 10 and 16 months of age, unveil motor impairments exclusive to P8 α-SynTg mice, a phenomenon conspicuously absent in α-SynTg mice. These findings suggest a synergistic interplay between heightened α-Syn levels and the aging process, resulting in motor deficits. These motor disturbances correlate with reduced dopamine (DA) levels, increased DA turnover, synaptic terminal loss, and notably, the depletion of dopaminergic neurons in the substantia nigra and noradrenergic neurons in the locus coeruleus. Furthermore, P8 α-SynTg mice exhibit alterations in gut transit time, mirroring early PD symptoms. In summary, P8 α-SynTg mice effectively replicate parkinsonian phenotypes by combining α-Syn transgene expression with accelerated aging. This model offers valuable insights into the understanding of PD and serves as a valuable platform for further research.

Glial senescence enhances α-synuclein pathology owing to its insufficient clearance caused by autophagy dysfunction

Parkinson’s disease (PD) is characterized by the pathological accumulation of α-synuclein (α-syn) and loss of dopaminergic neurons in the substantia nigra. Aging is a significant risk factor for PD. The accumulation of senescent glial cells in the aged brain contributes to PD progression by inducing chronic neuroinflammatory processes. However, although the insufficient degradation of α-syn aggregates results in PD deterioration, the possible alteration in the ability of α-syn clearance in senescent glia has received little attention. In this study, we investigated how aging and glial senescence affect the capacity of α-syn clearance. We found that following the intra-striatal injection of human α-syn (hu-α-syn) preformed fibril, hu-α-syn pathology persisted more in aged mice compared with younger mice and that aged microglia exhibited greater accumulation of hu-α-syn than younger microglia. Moreover, in vitro assay revealed that the clearance of hu-α-syn was primarily dependent on the autophagy-lysosome system rather than on the ubiquitin-proteasome system and that the capacity of hu-α-syn clearance was diminished in senescent glia because of autophagy-lysosome system dysfunction. Overall, this study provides new insights into the role of senescent glia in PD pathogenesis.

GBA-associated Parkinson's disease in Hungary: clinical features and genetic insights.

Parkinson's disease (PD) has a complex genetic background involving both rare and common genetic variants. Although a small percentage of cases show a clear Mendelian inheritance pattern, it is much more relevant to identify patients who present with a complex genetic profile of risk variants with different severity. The ß-glucocerebrosidase coding gene (GBA1) is recognized as the most frequent genetic risk factor for PD and Lewy body dementia, irrespective of reduction of the enzyme activity due to genetic variants. In a selected cohort of 190 Hungarian patients with clinical signs of PD and suspected genetic risk, we performed the genetic testing of the GBA1 gene. As other genetic hits can modify clinical features, we also screened for additional rare variants in other neurodegenerative genes and assessed the APOE-ε genotype of the patients. In our cohort, we identified 29 GBA1 rare variant (RV) carriers. Out of the six different detected RVs, the highly debated E365K and T408M variants are composed of the majority of them (22 out of 32). Three patients carried two GBA1 variants, and an additional three patients carried rare variants in other neurodegenerative genes (SMPD1, SPG11, and SNCA). We did not observe differences in age at onset or other clinical features of the patients carrying two GBA1 variants or patients carrying heterozygous APOE-ε4 allele. We need further studies to better understand the drivers of clinical differences in these patients, as this could have important therapeutic implications.

GWAS OF BRAIN ENDOPHENOTYPES: ASSOCIATION OF AUTOPSY-BASED LEWY BODY COUNTS WITH MOVEMENT DISORDER RISK LOCI

Abstract We performed a genome wide association study (GWAS) of neocortical Lewy body density. Case material were 308 autopsies of Japanese-American men (mean age at death 87.5 years; 11% with mild, and 30% with severe cognitive impairment prior to death). Lewy bodies were assessed by manual count of alpha-synuclein stained neocortical sections from the frontal, temporal, parietal, and occipital lobes. Genetic association was tested by linear models controlling for age at death assuming an additive genotypic effect. Top hits include a locus on chromosome 1q32 previously associated with amyotrophic lateral sclerosis (p=5.8e-8), intronic variants on the dopaminergic neuron axonal guidance gene EPHB1 previously associated with Parkinson’s disease (PD) (p=8.4e-6), and a locus containing two independent intron 1 variants on CSMD1, a known risk factor for autosomal dominant PD (p=1.5e-6). Complement inhibitor protein CSMD1 is a type 1 transmembrane cell adhesion molecule implicated in axonal guidance and the development, maintenance, and pruning of synapses in the adult brain. Intermediate hits include genes encoding cell adhesion molecules and a second complement inhibitor implicated in the regulation of synapses (TRAPPC9). This converging evidence points to cell adhesion proteins and complement mediated synaptic regulation in the etiology of Lewy body lesions.

Research on the bidirectional relationships between sleep and parkinsons disease

Parkinsons disease (PD) is the second most prevalent neurodegenerative disease in the world, and among its most common symptoms is sleep disruption. Due to the glymphatic systems role in removing alpha-synuclein and other substances related to PD pathogenesis, glymphatic dysfunction has been established as a risk factor for PD. Though sleep disturbance is often a symptom of PD, its role in increasing glymphatic clearance has led some researchers to believe that sleep disturbance could also be a risk factor for PD. This review will examine the scientific literature that suggests links between sleep disruption, PD pathology, or glymphatic dysfunction, as well as address some of the limitations in affirming such relationships. According to current research, sleep disruption is a common nonmotor symptom of PD but can also lead to reduced glymphatic function, which in turn reduces alpha-synuclein clearance and advances PD pathogenesis. However, PD development could also impair glymphatic clearance by depolarizing AQP4 channels or reducing sleep duration and quality.

6PPD-quinone exposure induces neuronal mitochondrial dysfunction to exacerbate Lewy neurites formation induced by α-synuclein preformed fibrils seeding

The emerging toxicant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPD-Q) is of wide concern due to its ubiquitous occurrence and high toxicity. Despite regular human exposure, limited evidence exists about its presence in the body and potential health risks. Herein, we analyzed cerebrospinal fluid (CSF) samples from Parkinson's disease (PD) patients and controls. The CSF levels of 6PPD-Q were twice as high in PD patients compared to controls. Immunostaining assays performed with primary dopaminergic neurons confirm that 6PPD-Q at environmentally relevant concentrations can exacerbate the formation of Lewy neurites induced by α-synuclein preformed fibrils (α-syn PFF). Assessment of cellular respiration reveals a considerable decrease in neuronal spare respiratory and ATP-linked respiration, potentially due to changes in mitochondrial membrane potential. Moreover, 6PPD-Q-induced mitochondrial impairment correlates with an upsurge in mitochondrial reactive oxygen species (mROS), and Mito-TEMPO-driven scavenging of mROS can lessen the amount of pathologic phospho-serine 129 α-synuclein. Untargeted metabolomics provides supporting evidence for the connection between 6PPD-Q exposure and changes in neuronal metabolite profiles. In-depth targeted metabolomics further unveils an overall reduction in glycolysis metabolite pool and fluctuations in the quantity of TCA cycle intermediates. Given its potentially harmful attributes, the presence of 6PPD-Q in human brain could potentially be a risk factor for PD.