Title :
TMEM106B p .T185S regulates
TMEM106B protein levels: implications for frontotemporal dementia
Abstract :
- Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65
- In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 ( FTLD-TDP )
- Recently, a genome-wide association study identified the first FTLD-TDP genetic risk factor , in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD-TDP risk
- Intriguingly, the most significant association was in FTLD-TDP patients carrying progranulin ( GRN ) mutations
- Here, we investigated to what extent the coding variant , rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein ( PGRN ) biology and transmemb rane protein 106 B ( TMEM106B ) regulation
- First, we confirmed the association of TMEM106B variants with FTLD-TDP in a new cohort of GRN mutation carriers
- We next generated and characterized a TMEM106B-specific antibody for investigation of this protein
- Enzyme-linked immunoassay analysis of progra nulin protein levels showed similar effects upon T185 and S185 TMEM106B over-expression
- However, over-expression of T185 consistently led to higher TMEM106B protein levels than S185
- Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B , potentially due to differences in N-glycosylation at residue N183
- Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD-TDP risk
- We studied the p.T185S TMEM106B genetic variant previously implicated in frontotemporal dementia with TAR DNA binding protein 43 pathology caused by progranulin mutations
- Our cell culture studies provide evidence that the protective S185 isoform is degraded more rapidly than T185 TMEM106B , potentially due to differences in glycosylation
- These findings suggest that low TMEM106B levels might protect against FTLD-TDP in these patients