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Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies
Author(s) -
Krohn Lynne,
Öztürk Tuğba Nur,
Vanderperre Benoît,
Ouled Amar Bencheikh Bouchra,
Ruskey Jennifer A.,
Laurent Sandra B.,
Spiegelman Dan,
Postuma Ronald B.,
Arnulf Isabelle,
Hu Michele T. M.,
Dauvilliers Yves,
Högl Birgit,
Stefani Ambra,
Monaca Christelle Charley,
Plazzi Giuseppe,
Antelmi Elena,
FeriniStrambi Luigi,
Heidbreder Anna,
Rudakou Uladzislau,
Cochen De Cock Valérie,
Young Peter,
Wolf Pavlina,
Oliva Petra,
Zhang Xiaokui Kate,
Greenbaum Lior,
Liong Christopher,
Gag JeanFrançois,
Desautels Alex,
HassinBaer Sharon,
Montplaisir Jacques Y.,
Dupré Nicolas,
Rouleau Guy A.,
Fon Edward A.,
Trempe JeanFrançois,
Lamoureux Guillaume,
Alcalay Roy N.,
GanOr Ziv
Publication year - 2020
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25629
Subject(s) - synucleinopathies , locus (genetics) , transmembrane domain , lrrk2 , biology , genome wide association study , genetics , genetic association , homology modeling , genotype , parkinson's disease , gene , medicine , single nucleotide polymorphism , biochemistry , disease , alpha synuclein , mutation , enzyme
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;87:139–153