Lipid level alteration in human and cellular models of alpha synuclein mutations

Lipid profiles in biological fluids from patients with Parkinson’s disease (PD) are increasingly investigated in search of biomarkers. However, the lipid profiles in genetic PD remain to be determined, a gap of knowledge of particular interest in PD associated with mutant α-synuclein (SNCA), given the known relationship between this protein and lipids. The objective of this research is to identify serum lipid composition from SNCA A53T mutation carriers and to compare these alterations to those found in cells and transgenic mice carrying the same genetic mutation. We conducted an unbiased lipidomic analysis of 530 lipid species from 34 lipid classes in serum of 30 participants with SNCA mutation with and without PD and 30 healthy controls. The primary analysis was done between 22 PD patients with SNCA+ (SNCA+/PD+) and 30 controls using machine-learning algorithms and traditional statistics. We also analyzed the lipid composition of human clonal-cell lines and tissue from transgenic mice overexpressing the same SNCA mutation. We identified specific lipid classes that best discriminate between SNCA+/PD+ patients and healthy controls and found certain lipid species, mainly from the glycerophosphatidylcholine and triradylglycerol classes, that are most contributory to this discrimination. Most of these alterations were also present in human derived cells and transgenic mice carrying the same mutation. Our combination of lipidomic and machine learning analyses revealed alterations in glycerophosphatidylcholine and triradylglycerol in sera from PD patients as well as cells and tissues expressing mutant α-Syn. Further investigations are needed to establish the pathogenic significance of these α-Syn-associated lipid changes. © 2022, The Author(s)

Motor and Nonmotor Features of Carriers of the p.A53T Alpha-Synuclein Mutation: A Longitudinal Study

Background: G209A SNCA mutation carriers represent an important group of genetic PD. We describe motor and nonmotor features of G209A SNCA mutation carriers. Methods: Longitudinal clinical assessments over 2 years were collected in 22 symptomatic and 8 asymptomatic G209A SNCA mutation carriers. Motor and nonmotor rating scales were administered. Correlations were performed between clinical variables and disease duration or age. Penetrance was calculated using Kaplan-Meier survival curves. Results: Asymptomatic carriers did not manifest clear premotor symptoms, but symptomatic carriers often reported that olfactory dysfunction and rapid eye movement sleep behavior disorder preceded motor symptoms. Prominent motor decline and deterioration of autonomic and cognitive function occurred at follow-up; such nonmotor features correlated with disease duration, but not age. Disease penetrance was estimated at around 90%. Conclusions: This study may help to inform clinical trials and provide the basis for studies of disease modifiers in genetic synucleinopathy cohorts. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Societ

Motor and Nonmotor Features of Carriers of the p.A53T Alpha-Synuclein Mutation: A Longitudinal Study

Background: G209A SNCA mutation carriers represent an important group of genetic PD. We describe motor and nonmotor features of G209A SNCA mutation carriers. Methods: Longitudinal clinical assessments over 2 years were collected in 22 symptomatic and 8 asymptomatic G209A SNCA mutation carriers. Motor and nonmotor rating scales were administered. Correlations were performed between clinical variables and disease duration or age. Penetrance was calculated using Kaplan-Meier survival curves. Results: Asymptomatic carriers did not manifest clear premotor symptoms, but symptomatic carriers often reported that olfactory dysfunction and rapid eye movement sleep behavior disorder preceded motor symptoms. Prominent motor decline and deterioration of autonomic and cognitive function occurred at follow-up; such nonmotor features correlated with disease duration, but not age. Disease penetrance was estimated at around 90%. Conclusions: This study may help to inform clinical trials and provide the basis for studies of disease modifiers in genetic synucleinopathy cohorts. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Societ

Widespread Tau-Specific CD4 T Cell Reactivity in the General Population

Tau protein is found to be aggregated and hyperphosphorylated (p-tau) in many neurologic disorders, including Parkinson disease (PD) and related parkinsonisms, Alzheimer disease, traumatic brain injury, and even in normal aging. Although not known to produce autoimmune responses, we hypothesized that the appearance of aggregated tau and p-tau with disease could activate the immune system. We thus compared T cell responses to tau and p-tau–derived peptides between PD patients, age-matched healthy controls, and young healthy controls (<35 y old; who are less likely to have high levels of tau aggregates). All groups exhibited CD4+ T cell responses to tau-derived peptides, which were associated with secretion of IFN-γ, IL-5, and/or IL-4. The PD and control participants exhibited a similar magnitude and breadth of responses. Some tau-derived epitopes, consisting of both unmodified and p-tau residues, were more highly represented in PD participants. These results were verified in an independent set of PD and control donors (either age-matched or young controls). Thus, T cells recognizing tau epitopes escape central and peripheral tolerance in relatively high numbers, and the magnitude and nature of these responses are not modulated by age or PD disease

T cells from patients with Parkinson’s disease recognize α-synuclein peptides

Genetic studies have shown the association of Parkinson's disease with alleles of the major histocompatibility complex. Here we show that a defined set of peptides that are derived from α-synuclein, a protein aggregated in Parkinson's disease, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in patients with Parkinson's disease. These responses may explain the association of Parkinson's disease with specific major histocompatibility complex alleles

The relation between depression and parkin genotype: The CORE-PD study

Mutations in parkin are a known genetic risk factor for early onset Parkinson’s disease (EOPD) but their role in non-motor manifestations is not well established. Genetic factors for depression are similarly not well characterized. We investigate the role of parkin mutations in depression among those with EOPD and their relatives. We collected psychiatric information using the Patient Health Questionnaire and Beck Depression Inventory II on 328 genotyped individuals including 88 probands with early onset PD (41 with parkin mutations, 47 without) and 240 first and second-degree relatives without PD. Genotype was not associated with depression risk among probands. Among unaffected relatives of EOPD cases, only compound heterozygotes ( n = 4), and not heterozygotes, had significantly increased risk of depressed mood (OR = 14.1; 95% CI 1.2–163.4), moderate to severe depression (OR = 17.8; 95% CI 1.0–332.0), depression (score ≥ 15) on the Beck Depression Inventory II (BDI-II) (OR = 51.9; 95% CI 4.1–657.4), and BDI-II total depression score ( β = 8.4; 95% CI 2.4–11.3) compared to those without parkin mutations. Relatives of EOPD cases with compound heterozygous mutations and without diagnosed PD may have a higher risk of depression compared to relatives without parkin mutations. These findings support evidence of a genetic contribution to depression and may extend the phenotypic spectrum of parkin mutations to include non-motor manifestations that precede the development of P

Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies

Objective: The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications. Methods: Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function. Results: Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants. Interpretation: Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139\u2013153

The relation between depression and parkin genotype: The CORE-PD study

BACKGROUND: Mutations in parkin are a known genetic risk factor for early-onset Parkinson’s disease (EOPD) but their role in non-motor manifestations is not well established. Genetic factors for depression are similarly not well characterized. We investigate the role of parkin mutations in depression among those with EOPD and their relatives. METHODS: We collected psychiatric information using the Patient Health Questionnaire and Beck Depression Inventory II on 328 genotyped individuals including 88 probands with early onset PD (41 with parkin mutations, 47 without) and 240 first and second degree relatives without PD. RESULTS: Genotype was not associated with depression risk among probands. Among unaffected relatives of EOPD cases, only compound heterozygotes (n=4), and not heterozygotes, had significantly increased risk of depressed mood (OR=14.1; 95% CI 1.2–163.4), moderate to severe depression (OR=17.8; 95% CI 1.0–332.0), depression (score ≥15) on the Beck Depression Inventory II (BDI-II) (OR=51.9; 95% CI 4.1–657.4), and BDI-II total depression score (β=8.4; 95% CI 2.4–11.3) compared to those without parkin mutations. CONCLUSIONS: Relatives of EOPD cases with compound heterozygous mutations and without diagnosed PD may have a higher risk of depression compared to relatives without parkin mutations. These findings support evidence of a genetic contribution to depression and may extend the phenotypic spectrum of parkin mutations to include non-motor manifestations that precede the development of PD

Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development