Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies: Annals of Neurology

L. Krohn, T.N. Öztürk, B. Vanderperre, B. Ouled Amar Bencheikh, J.A. Ruskey, S.B. Laurent, D. Spiegelman, R.B. Postuma, I. Arnulf, M.T.M. Hu, Y. Dauvilliers, B. Högl, A. Stefani, C.C. Monaca, G. Plazzi, E. Antelmi, L. Ferini-Strambi, A. Heidbreder, U. Rudakou, V. Cochen De CockP. Young, P. Wolf, P. Oliva, X.K. Zhang, L. Greenbaum, C. Liong, J.-F. Gagnon, A. Desautels, S. Hassin-Baer, J.Y. Montplaisir, N. Dupré, G.A. Rouleau, E.A. Fon, J.-F. Trempe, G. Lamoureux, R.N. Alcalay, Z. Gan-Or

Research output: Contribution to journalArticlepeer-review

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. © 2019 American Neurological Association
Original languageEnglish
Pages (from-to)139-153
Number of pages15
JournalAnn. Neurol.
Volume87
Issue number1
DOIs
Publication statusPublished - 2020

Keywords

  • glucosylceramidase
  • potassium channel
  • TMEM175 protein, human
  • aged
  • Article
  • controlled study
  • enzyme activity
  • female
  • gene locus
  • genetic analysis
  • genome-wide association study
  • genotype
  • human
  • human cell
  • hydrophobicity
  • lysosome
  • major clinical study
  • male
  • molecular dynamics
  • parasomnia
  • Parkinson disease
  • priority journal
  • protein localization
  • sequence homology
  • simulation
  • structure analysis
  • synucleinopathy
  • adult
  • case control study
  • genetic predisposition
  • genetics
  • metabolism
  • middle aged
  • molecular model
  • pathophysiology
  • physiology
  • single nucleotide polymorphism
  • Adult
  • Aged
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Glucosylceramidase
  • Humans
  • Lysosomes
  • Male
  • Middle Aged
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Parkinson Disease
  • Polymorphism, Single Nucleotide
  • Potassium Channels
  • REM Sleep Behavior Disorder
  • Synucleinopathies

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