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Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies

Lynne Krohn 1, 2 Tuğba Nur Öztürk 3, 4, 5 Benoît Vanderperre 2, 6 Bouchra Ouled Amar Bencheikh 2, 6 Jennifer Ruskey 2, 6 Sandra Laurent 2, 6 Dan Spiegelman 2, 6 Ronald Postuma 2, 6 Isabelle Arnulf 7, 8 Michele Hu 9, 10 Yves Dauvilliers 11, 12 Birgit Högl 13 Ambra Stefani 13 Christelle Charley Monaca 14 Giuseppe Plazzi 15, 16 Elena Antelmi 15, 16 Luigi Ferini-Strambi 17 Anna Heidbreder 18 Uladzislau Rudakou 1, 2 Valérie Cochen de Cock 19, 20 Peter Young 21 Pavlina Wolf 22 Petra Oliva 22 Xiaokui Kate Zhang 22 Lior Greenbaum 23, 24, 25 Christopher Liong 26 Jean-François Gagnon 27, 28 Alex Desautels 27, 29 Sharon Hassin-Baer 25, 26, 24 Jacques Montplaisir 27, 30 Nicolas Dupré 29, 31 Guy Rouleau 1, 2, 32 Edward Fon 2, 32 Jean-François Trempe 33 Guillaume Lamoureux 3, 4, 5, 34 Roy Alcalay 26, 27 Ziv Gan-Or 1, 2, 6 
Abstract : 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.
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https://hal.umontpellier.fr/hal-03374526
Contributeur : Nathalie Salvy-Córdoba Connectez-vous pour contacter le contributeur
Soumis le : mardi 12 octobre 2021 - 10:53:39
Dernière modification le : vendredi 9 septembre 2022 - 10:20:08

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Lynne Krohn, Tuğba Nur Öztürk, Benoît Vanderperre, Bouchra Ouled Amar Bencheikh, Jennifer Ruskey, et al.. Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies. Annals of Neurology, Wiley, 2019, 87 (1), pp.139-153. ⟨10.1002/ana.25629⟩. ⟨hal-03374526⟩

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