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Article Dans Une Revue Annals of Neurology Année : 2019

Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies

1 Department of Human Genetics [Montréal]
2 Montreal Neurological Institute and Hospital
3 Concordia University [Montreal]
4 Centre for Research in Molecular Modeling and Department of Chemistry & Biochemistry
5 PROTEO, The Quebec Network for Research on Protein Function, Engineering, and Applications
6 Department of Neurology and Neurosurgery [Montreal]
7 CHU Pitié-Salpêtrière [AP-HP]
8 ICM - Institut du Cerveau = Paris Brain Institute
9 Department of Physiology, Anatomy and Genetics [Oxford]
10 Nuffield Department of Clinical Neurosciences [Oxford]
11 Hôpital Gui de Chauliac [CHU Montpellier]
12 PSNREC - Neuropsychiatrie : recherche épidémiologique et clinique
13 Universität Innsbruck [Innsbruck]
14 CHRU Lille - Service de neurophysiologie clinique
15 UNIBO - Alma Mater Studiorum Università di Bologna = University of Bologna
16 Institute of Neurological Sciences of Bologna IRCCS
17 UniSR - Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie]
18 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
19 Clinique Beau Soleil [Montpellier]
20 EuroMov - Euromov
21 UKM - University Hospital Münster - Universitaetsklinikum Muenster [Germany]
22 Sanofi Genzyme
23 The Danek Gertner Institute of Genetics, Chaim Sheba Medical Center
24 Chaim Sheba Medical Center
25 Sackler Faculty of Medicine
26 Columbia University College of Physicians and Surgeons
27 Center for advanced research in sleep medicine, Montreal
28 UQAM - Université du Québec à Montréal = University of Québec in Montréal
29 Axe Neurosciences [CHU Québec]
30 Research Center of CIUSSS of the North of Montreal and Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada
31 Laval University Medical center
32 MUHC - McGill University Health Center [Montreal]
33 Department of Pharmacology and Therapeutics [Montréal]
34 CCIB - Center for Computational and Integrative Biology [Camden]
Ambra Stefani
Pavlina Wolf
  • Fonction : Auteur
Petra Oliva
  • Fonction : Auteur

Résumé

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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Dates et versions

hal-03374526 , version 1 (12-10-2021)

Identifiants

Citer

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, 2019, 87 (1), pp.139-153. ⟨10.1002/ana.25629⟩. ⟨hal-03374526⟩
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