Association of Rare Variants in ARSA with Parkinson's Disease

Abstract

BackgroundSeveral lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and ARSA remains unclear.ObjectivesTo study rare ARSA variants in PD.MethodsTo study rare ARSA variants (minor allele frequency < 0.01) in PD, we performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by a meta‐analysis.ResultsWe found evidence for associations between functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each) and in the meta‐analysis (P = 0.042). We also found an association between loss‐of‐function variants and PD in the United Kingdom Biobank cohort (P = 0.005) and in the meta‐analysis (P = 0.049). These results should be interpreted with caution as no association survived multiple comparisons correction. Additionally, we describe two families with potential co‐segregation of ARSA p.E382K and PD.ConclusionsRare functional and loss‐of‐function ARSA variants may be associated with PD. Further replications in large case–control/familial cohorts are required. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease

“…On the other hand, we noted a significant elevation in four lipids of the lysophosphatidylcholine class, which play a role in neuron demyelination ( Figure 3B , C ) 44,45 . Along the same lines, of the few proteins significantly depleted from CSF in LMD patients, several are involved in critical processes of normal neuron function, including GRIA4 (learning and memory) 46 , ARSA (essential enzyme regulating myelination) 47,48 , THY1 (axon regeneration) 49 , CDH4 (neuronal outgrowth) 50 , NPTXR (synaptic activity) 51 , neurotransmitters TAC1 and TAC3 (behavioral responses) ( Figure 3D ) 52 . Principal component analysis (PCA) of proteomic and lipidomic profiling highlights the separation of samples from patients with short survival (LMD-3 and LMD-4) from the rare patient with long survival (LMD-1 and LMD-2) and from the non-LMD controls ( Supplemental Figure 6A-B ).…”

Joint-tissue integrative analysis identifies high-risk genes for Parkinson’s disease

“…The Manhattan plot represents the risk genes of PD screened by MR-JTI from 13 brain regions ( Figure 2 and Supplementary Figure 1 ). Among PD-related genes in the brain substantia area, ARSA ( Senkevich et al, 2023 ), KANSL1-AS1 ( Lona-Durazo et al, 2023 ), FAM47E ( Blauwendraat et al, 2019 ), and ARHGAP27 ( Saeed, 2018 ) have been reported to be risk loci that contribute to the development of PD. The genetic alteration among NMRN1 ( Fuchs et al, 2007 ), CRHR1 ( Cheng et al, 2020 ; Rasmi et al, 2023 ), and HLA-DRB1 ( Le Guen et al, 2023 ) in the brain cortex increased the risk of PD.…”