Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease

Abstract

Multiple genome-wide association studies (GWAS) in Parkinson disease (PD) have identified a signal at chromosome 4p16.3; however, the causal variant has not been established for this locus. Deep investigation of the region resulted in one identified variant, the rs34311866 missense SNP (p.M393T) in TMEM175, which is 20 orders of magnitude more significant than any other SNP in the region. Because TMEM175 is a lysosomal gene that has been shown to influence α-synuclein phosphorylation and autophagy, the p.M393T variant is an attractive candidate, and we have examined its effect on TMEM175 protein and PD-related biology. After knocking down each of the genes located under the GWAS peak via multiple shRNAs, only TMEM175 was found to consistently influence accumulation of phosphorylated α-synuclein (p-α-syn). Examination of the p.M393T variant showed effects on TMEM175 function that were intermediate between the wild-type (WT) and knockout phenotypes, with reduced regulation of lysosomal pH in response to starvation and minor changes in clearance of autophagy substrates, reduced lysosomal localization, and increased accumulation of p-α-syn. Finally, overexpression of WT TMEM175 protein reduced p-α-syn, while overexpression of the p.M393T variant resulted in no change in α-synuclein phosphorylation. These results suggest that the main signal in the chromosome 4p16.3 PD risk locus is driven by the TMEM175 p.M393T variant. Modulation of TMEM175 may impact α-synuclein biology and therefore may be a rational therapeutic strategy for PD.

Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

“…Depletion of TMEM175, another lysosomal gene associated with PD, significantly decreases protein expression and enzyme activity of Cathepsin B in rat hippocampal neurons (Sarah Jinn et al 2017;S. Jinn et al 2019).…”

Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

“…17 More recently, it was demonstrated that the PD-associated TMEM175 coding variant p.M393T was associated with RBD and potentially affects the activity of the lysosomal enzyme glucocerebrosidase (encoded by GBA). 15,54 Therefore, it is possible that some genetic variants are relevant for all types of synucleinopathy, with and without RBD, but other variants are specifically relevant for RBD-associated synucleinopathy. Currently, the division between PD and DLB is somewhat arbitrary, determined by a cutoff of one year between the onset of parkinsonism and the onset of dementia.…”

The Parkinson’s Disease GWAS Locus Browser

“…GWAS has identified a number of these pleiotropic genes at various loci such as SNCA (locus 23), GBA (locus1), LRRK2 (locus 49) and VPS13C (locus 59). Current evidence suggests that TMEM175 (locus 19 [10]), CTSB (locus 37 [8,13]) and GCH1 (locus 56, [58]) are also pleiotropic and lead to PD by multiple mechanisms. Our goal is to provide the PD research community with a tool that catalogs all significant PD GWAS signals and helps prioritize the genes at each locus for functional studies.…”

“…For PD, these approaches include using single cell RNA-seq to determine gene expression in relevant cell populations [7], transcriptomewide association studies [8], and quantitative trait loci (QTL) [3]. Others have functionally prioritized a single locus (SNCA [9] and TMEM175 [10]) but these functional single locus experiments often do not scale up to loci with many genes. Other non-disease specific pipelines have been developed using epigenetic and chromatin conformation datasets in addition to expression QTL (eQTL) data [11,12], however some disease specific interpretation will be needed.…”