Journal
ANNALS OF NEUROLOGY
Volume 87, Issue 1, Pages 139-153Publisher
WILEY
DOI: 10.1002/ana.25629
Keywords
-
Categories
Funding
- Michael J. Fox Foundation
- Canadian Consortium on Neurodegeneration in Aging
- Canadian Glycomics Network
- Canada First Research Excellence Fund
- Parkinson's Foundation
- NIH (National Institute of Neurological Disorders and Stroke, NINDS) [K02NS080915]
- NIH (National Center for Advancing Translational Sciences, NCATS) [UL1TR000040]
- Brookdale Foundation
- Canadian Institutes for Health Research (CIHR)
- W. Garfield Weston Foundation
- CIHR fellowship program [MFE 152571]
- Natural Sciences and Engineering Research Council [RGPIN 355789]
- Fonds de recherche du Quebec-Sante Chercheurs-boursiers award
- Parkinson Quebec
- Parkinson Canada New Investigator Award
- Canada Foundation for Innovation
- NanoQuebec
- Reseau de medecine genetique appliquee (RMGA)
- Fonds de recherche du Quebec-Nature et technologies
- Common Fund of the Office of the Director of the NIH
- National Cancer Institute
- National Human Genome Research Institute
- National Heart, Lung, and Blood Institute
- National Institute on Drug Abuse
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke
Ask authors/readers for more resources
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 2019
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available