Are rare heterozygous SYNJ1 variants associated with Parkinson's disease?

Previous studies have established that rare biallelic SYNJ1 mutations cause autosomal recessive parkinsonism and Parkinson's disease (PD). We analyzed 8165 PD cases, 818 early-onset-PD (EOPD, < 50 years) and 70,363 controls. Burden meta-analysis revealed an association between rare nonsynonymous variants and variants with high Combined Annotation-Dependent Depletion score (> 20) in the Sac1 SYNJ1 domain and PD (Pfdr = 0.

Plasma glucosylceramide levels are regulated by and are not involved in Parkinson's disease pathogenesis.

variants and decreased glucocerebrosidase (GCase) activity are implicated in Parkinson's disease (PD). We investigated the hypothesis that increased levels of glucosylceramide (GlcCer), one of GCase main substrates, are involved in PD pathogenesis. Using multiple genetic methods, we show that not , is the main regulator of plasma GlcCer levels, yet it is not involved in PD pathogenesis.

Are rare heterozygous variants associated with Parkinson's disease?

Previous studies have suggested that rare biallelic mutations may cause autosomal recessive parkinsonism and Parkinson's disease (PD). Our study explored the impact of rare variants in non-familial settings, including 8,165 PD cases, 818 early-onset PD (EOPD, <50 years) and 70,363 controls. Burden meta-analysis using optimized sequence Kernel association test (SKAT-O) revealed an association between rare nonsynonymous variants in the Sac1 SYNJ1 domain and PD (P=0.

The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.

Background: Variants in the gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson's disease (PD). However, neither the specific variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis.

The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.

Variants in the gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson's disease (PD). However, neither the specific variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis.

Lack of genetic evidence for NLRP3-inflammasome involvement in Parkinson's disease pathogenesis.

Activation of the NLRP3-inflammasome has been implicated in Parkinson's disease based on and studies. Clinical trials targeting the NLRP3-inflammasome in Parkinson's disease are ongoing. However, the evidence supporting NLRP3's involvement in Parkinson's disease from human genetics data is limited.

4R-Tau seeding activity unravels molecular subtypes in patients with Progressive Supranuclear Palsy.

Progressive Supranuclear palsy (PSP) is a 4-repeat (4-R) tauopathy. We hypothesized that the molecular diversity of tau could explain the heterogeneity seen in PSP disease progression. To test this hypothesis, we performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients.

Machine learning nominates the inositol pathway and novel genes in Parkinson's disease.

There are 78 loci associated with Parkinson's disease in the most recent genome-wide association study (GWAS), yet the specific genes driving these associations are mostly unknown. Herein, we aimed to nominate the top candidate gene from each Parkinson's disease locus and identify variants and pathways potentially involved in Parkinson's disease. We trained a machine learning model to predict Parkinson's disease-associated genes from GWAS loci using genomic, transcriptomic and epigenomic data from brain tissues and dopaminergic neurons.

DNA Methylation Age Acceleration as a Potential Biomarker for Early Onset of Rapid Eye Movement Sleep Behavior Disorder.

Rapid eye movement sleep behavior disorder (RBD) is the strongest prodromal marker for α-synucleinopathies. The Horvath DNA methylation age (DNAm-age) is an epigenetic clock reflecting biological aging. We found an association of DNAm-age acceleration with RBD age at onset at baseline (N = 162, B = -0.

MerTK is a mediator of alpha-synuclein fibril uptake by human microglia.

Mer tyrosine kinase (MerTK) is a receptor tyrosine kinase that mediates non-inflammatory, homeostatic phagocytosis of diverse types of cellular debris. Highly expressed on the surface of microglial cells, MerTK is of importance in brain development, homeostasis, plasticity and disease. Yet, involvement of this receptor in the clearance of protein aggregates that accumulate with ageing and in neurodegenerative diseases has yet to be defined.

Association of Rare Variants in ARSA with Parkinson's Disease.

Background: Several lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and ARSA remains unclear.

Objectives: To study rare ARSA variants in PD.

Methods: To study rare ARSA variants (minor allele frequency < 0.

Potential Protective Link Between Type I Diabetes and Parkinson's Disease Risk and Progression.

Background: Epidemiological studies suggested an association between Parkinson's disease (PD) and type 2 diabetes, but less is known about type 1 diabetes (T1D) and PD.

Objective: This study sought to explore the association between T1D and PD.

Methods: We used Mendelian randomization, linkage disequilibrium score regression, and multi-tissue transcriptome-wide analysis to examine the association between PD and T1D.

Association of rare variants in with Parkinson's disease.

Background: Several lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and , which encodes for the enzyme arylsulfatase A, remains controversial.

Objectives: To evaluate the association between rare variants and PD.

Methods: To study possible association of rare variants (minor allele frequency<0.

Genetic mechanism vs genetic subtypes: The example of GBA.

Genetic variants in GBA, encoding the lysosomal enzyme glucocerebrosidase (GCase), are common risk factors for Parkinson's disease (PD). Genotype-phenotype studies have demonstrated that different types of GBA variants have differential effects on the phenotype. Variants could be classified as mild or severe depending on the type of Gaucher disease they cause in the biallelic state.

GALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson's disease.

The association between glucocerebrosidase, encoded by GBA, and Parkinson's disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway.

Investigation of the causal relationship between ALS and autoimmune disorders: a Mendelian randomization study.

Background: Epidemiological studies have reported an association between amyotrophic lateral sclerosis (ALS) and different autoimmune disorders. This study aims to explore the causal relationship between autoimmune disorders and ALS using Mendelian randomization (MR).

Methods: To test the genetically predicted effects of liability towards immune-related outcomes on ALS risk, we used summary statistics from the largest European genome-wide association studies (GWAS) for these disorders in a two-sample MR setting.