Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• The TMEM175/GAK/DGKQ locus is a significant genetic risk factor for Parkinson disease (PD).
• Identifying specific variants within this locus is crucial for understanding PD etiology.

Purpose of the Study:

• To pinpoint disease-associated variants in the TMEM175/GAK/DGKQ locus.
• To investigate the functional implications of these variants on TMEM175 protein and GCase activity.

Main Methods:

• Comprehensive sequencing and genotyping of the TMEM175/GAK/DGKQ locus in PD, RBD, and control cohorts.
• Statistical association analyses, including regression models and meta-analysis.
• In silico analyses (homology modeling, molecular dynamics) and in vitro experiments (lysosomal localization) to assess variant effects.

Main Results:

• Two TMEM175 coding variants, p.M393T and p.Q65P, were significantly associated with PD risk.
• The p.M393T variant was also linked to rapid eye movement sleep behavior disorder (RBD) and reduced glucocerebrosidase (GCase) activity.
• Structural modeling suggested p.M393T may destabilize TMEM175, potentially impairing its function, while p.Q65P might enhance protein stability and ion conductance.

Conclusions:

• Coding variants in TMEM175 are likely the primary drivers of the genetic association at this locus.
• The observed effects on GCase activity suggest a potential mechanism linking TMEM175 variants to neurodegenerative diseases like PD.