1. Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies
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Uladzislau Rudakou, Edward A. Fon, Petra Oliva, Guy A. Rouleau, Yves Dauvilliers, Elena Antelmi, Birgit Högl, Anna Heidbreder, Jean-François Trempe, Christopher Liong, Bouchra Ouled Amar Bencheikh, Pavlina Wolf, Isabelle Arnulf, Luigi Ferini-Strambi, A. Desautels, Jennifer A. Ruskey, Peter Young, Nicolas Dupré, Valérie Cochen De Cock, Giuseppe Plazzi, Lior Greenbaum, Michele T.M. Hu, Lynne Krohn, Roy N. Alcalay, Guillaume Lamoureux, Ziv Gan-Or, Xiaokui Kate Zhang, Jacques Montplaisir, S. Hassin-Baer, Dan Spiegelman, Ronald B. Postuma, Ambra Stefani, Jean-François Gagnon, Christelle Charley Monaca, Benoît Vanderperre, Sandra B. Laurent, Tugba N. Ozturk, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Montreal Neurological Institute and Hospital, Concordia University [Montreal], Centre for Research in Molecular Modeling and Department of Chemistry & Biochemistry, PROTEO, The Quebec Network for Research on Protein Function, Engineering, and Applications, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)-Université de Sherbrooke (UdeS)-Université Laval [Québec] (ULaval)-McGill University = Université McGill [Montréal, Canada]-University of Ottawa [Ottawa]-Université du Québec à Trois-Rivières (UQTR)-Université de Montréal (UdeM)-TransBiotech, Lévis-Concordia University [Montreal]-Université du Québec à Montréal = University of Québec in Montréal (UQAM), Department of Neurology and Neurosurgery [Montreal], McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford [Oxford], Nuffield Department of Clinical Neurosciences [Oxford], Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universität Innsbruck [Innsbruck], Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Alma Mater Studiorum University of Bologna (UNIBO), Institute of Neurological Sciences of Bologna IRCCS, Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University of Münster, Clinique Beau Soleil [Montpellier], Euromov (EuroMov), Université de Montpellier (UM), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Sanofi Genzyme, The Danek Gertner Institute of Genetics, Chaim Sheba Medical Center, Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Columbia University College of Physicians and Surgeons, Center for advanced research in sleep medicine, Montreal, Université de Montréal (UdeM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Research Center of CIUSSS of the North of Montreal and Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada, Laval University Medical center, Université Laval [Québec] (ULaval), McGill University Health Center [Montreal] (MUHC), Department of Pharmacology and Therapeutics [Montréal], Center for Computational and Integrative Biology [Camden] (CCIB), Rutgers University [Camden], Rutgers University System (Rutgers)-Rutgers University System (Rutgers), Krohn, L., Ozturk, T. N., Vanderperre, B., Ouled Amar Bencheikh, B., Ruskey, J. A., Laurent, S. B., Spiegelman, D., Postuma, R. B., Arnulf, I., M. T. M., Hu, Dauvilliers, Y., Hogl, B., Stefani, A., Monaca, C. C., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Heidbreder, A., Rudakou, U., Cochen De Cock, V., Young, P., Wolf, P., Oliva, P., Zhang, X. K., Greenbaum, L., Liong, C., Gagnon, J. -F., Desautels, A., Hassin-Baer, S., Montplaisir, J. Y., Dupre, N., Rouleau, G. A., Fon, E. A., Trempe, J. -F., Lamoureux, G., Alcalay, R. N., Gan-Or, Z., Krohn L., Ozturk T.N., Vanderperre B., Ouled Amar Bencheikh B., Ruskey J.A., Laurent S.B., Spiegelman D., Postuma R.B., Arnulf I., Hu M.T.M., Dauvilliers Y., Hogl B., Stefani A., Monaca C.C., Plazzi G., Antelmi E., Ferini-Strambi L., Heidbreder A., Rudakou U., Cochen De Cock V., Young P., Wolf P., Oliva P., Zhang X.K., Greenbaum L., Liong C., Gagnon J.-F., Desautels A., Hassin-Baer S., Montplaisir J.Y., Dupre N., Rouleau G.A., Fon E.A., Trempe J.-F., Lamoureux G., Alcalay R.N., and Gan-Or Z.
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0301 basic medicine ,Male ,Models, Molecular ,Potassium Channels ,Synucleinopathies ,Genome-wide association study ,REM Sleep Behavior Disorder ,MESH: Glucosylceramidase ,MESH: Genotype ,0302 clinical medicine ,TMEM175/GAK/DGKQ ,genetics ,MESH: Molecular Dynamics Simulation ,Parkinson ,Genetics ,MESH: Aged ,MESH: Middle Aged ,synucleinopaties ,MESH: Polymorphism, Single Nucleotide ,MESH: Genetic Predisposition to Disease ,Parkinson Disease ,MESH: Potassium Channels ,Middle Aged ,MESH: Case-Control Studies ,Transmembrane protein ,Neurology ,MESH: Synucleinopathies ,Glucosylceramidase ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Female ,synucleinopathies ,MESH: Models, Molecular ,Adult ,Genotype ,Locus (genetics) ,Single-nucleotide polymorphism ,Biology ,Molecular Dynamics Simulation ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Humans ,Genetic Predisposition to Disease ,Homology modeling ,Genetic association ,Aged ,MESH: Humans ,MESH: Adult ,MESH: Male ,030104 developmental biology ,REM sleep behavior disorder ,MESH: REM Sleep Behavior Disorder ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Case-Control Studies ,Neurology (clinical) ,Lysosomes ,Glucocerebrosidase ,MESH: Female ,030217 neurology & neurosurgery ,synucleinopathie ,MESH: Parkinson Disease ,MESH: Lysosomes - Abstract
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.
- Published
- 2018