GBA1 variants and decreased glucocerebrosidase activity are implicated in Parkinson's disease (PD). We investigated the hypothesis that increased levels of glucosylceramide (GlcCer), a main substrate of glucocerebrosidase, are involved in PD pathogenesis. Using multiple genetic methods, we show that ATPase phospholipid transporting 10D (ATP10D), not GBA1, is the main regulator of plasma GlcCer levels, yet it is not involved in PD pathogenesis.
View Article and Find Full Text PDFObservation studies suggest that coffee consumption may lower the risk of Parkinson's disease (PD). The aim of this study was to explore the causal relationship and genetic association between coffee consumption and the age-at-onset (AAO), risk, and progression of PD. Using Mendelian randomization, we identified a significant association between coffee consumption and delayed PD AAO (IVW: OR, 1.
View Article and Find Full Text PDFPolygenic risk scores (PRS) in Parkinson's disease (PD) are associated with disease risk. Recently, pathway-specific PRS have been created to take advantage of annotations inking variants to biological pathways or cell types. Here, we investigated 8 biological pathways or regions of open chromatin using pathway-specific PRS: alpha-synuclein pathway, adaptive immunity, innate immunity, lysosomal pathway1, endocytic membrane-trafficking pathway, mitochondrial pathway, microglial open chromatin single nucleotide polymorphisms (SNPs), and monocyte open chromatin SNPs.
View Article and Find Full Text PDFParkinson disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy are synucleinopathies, characterized by neuronal loss, gliosis and the abnormal deposition of α-synuclein in vulnerable areas of the nervous system. Neurodegeneration begins however several years before clinical onset of motor, cognitive or autonomic symptoms. The isolated form of REM sleep behavior disorder (RBD), a parasomnia with dream enactment behaviors and excessive muscle activity during REM sleep, is an early stage synucleinopathy.
View Article and Find Full Text PDFDepending on zygosity and the specific change, different variants in the GBA1 gene can cause Parkinson's disease (PD, PARK-GBA1) with reduced penetrance, act as genetic risk factors for PD or parkinsonism, and/or lead to Gaucher's disease (GD). This MDSGene systematic literature review covers 27,963 patients carrying GBA1 variants from 1082 publications with 794 variants, including 13,342 patients with PD or other forms of parkinsonism. It provides a comprehensive overview of demographic, clinical, and genetic findings from an ethnically diverse sample originating from 82 countries across five continents.
View Article and Find Full Text PDFTemporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is associated with a complex genetic architecture, but the translation from genetic risk factors to brain vulnerability remains unclear. Here, we examined associations between epilepsy-related polygenic risk scores for HS (PRS-HS) and brain structure in a large sample of neurotypical children, and correlated these signatures with case-control findings in in multicentric cohorts of patients with TLE-HS. Imaging-genetic analyses revealed PRS-related cortical thinning in temporo-parietal and fronto-central regions, strongly anchored to distinct functional and structural network epicentres.
View Article and Find Full Text PDFBlood-based biomarkers for Alzheimer's disease (AD) pathology have been intensively investigated as markers for AD-related neurodegeneration. Comorbid AD pathology is common in dementia with Lewy bodies (DLB). Accordingly, we hypothesized that plasma biomarkers associated with AD pathology might be useful to predict DLB in a cohort of idiopathic/isolated REM sleep behavior disorder (iRBD), an incipient synucleinopathy.
View Article and Find Full Text PDFInborn errors of selenoprotein expression arise from deleterious variants in genes encoding selenoproteins or selenoprotein biosynthetic factors, some of which are associated with neurodegenerative disorders. This study shows that bi-allelic selenocysteine tRNA-specific eukaryotic elongation factor (EEFSEC) variants cause selenoprotein deficiency, leading to progressive neurodegeneration. EEFSEC deficiency, an autosomal recessive disorder, manifests with global developmental delay, progressive spasticity, ataxia, and seizures.
View Article and Find Full Text PDFPurpose: Heterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST.
Methods: Targeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder.
The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014-2019; 2019-2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them.
View Article and Find Full Text PDFExpert Rev Mol Diagn
November 2024
Variants in GBA1 are important genetic risk factors in Parkinson's disease (PD). GBA1 T369M has been linked to an ∼80 % increased PD risk but the reports are conflicting and the relevance of GBA1 variants in different populations varies. A lack of association between T369M and PD in the Swedish population was recently reported but needs further validation.
View Article and Find Full Text PDFPrevious 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.
View Article and Find Full Text PDFvariants 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.
View Article and Find Full Text PDFNeurol Neuroimmunol Neuroinflamm
November 2024
Background And Objectives: Idiopathic/isolated REM sleep behavior disorder (iRBD) has been strongly linked to neurodegenerative synucleinopathies such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. However, there have been increasing reports of RBD as a presenting feature of serious and treatable autoimmune syndromes, particularly IGLON5. This study's objective was to investigate the frequency of autoantibodies in a large cohort of participants with iRBD.
View Article and Find Full Text PDFGlucocerebrosidase (GBA1) variants constitute numerically the most common known genetic risk factor for Parkinson's disease (PD) and are distributed worldwide. Access to GBA1 genotyping varies across the world and even regionally within countries. Guidelines for GBA1 variant counseling are evolving.
View Article and Find Full Text PDFDevelopmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells.
View Article and Find Full Text PDFBackground: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2.
Objectives: Our goal was to investigate the effects of genetic variants on risk and time to LID.
This scientific commentary refers to ‘Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson’s Disease Study’ by Westenberger (https://doi.org/10.1093/brain/awae188) and ‘Parkinson’s disease variant detection and disclosure: PD GENEration, a North American study’ by Cook .
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