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- Title
TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia.
- Authors
Nicholson, Alexandra M.; Finch, NiCole A.; Wojtas, Aleksandra; Baker, Matt C.; Perkerson, Ralph B.; Castanedes‐Casey, Monica; Rousseau, Linda; Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta; Hsiung, Ging‐Yuek R.; Mackenzie, Ian R.; Finger, Elizabeth; Boeve, Bradley F.; Ertekin‐Taner, Nilüfer; Graff‐Radford, Neill R.; Dickson, Dennis W.; Rademakers, Rosa
- 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 transmembrane 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 progranulin 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.
- Subjects
FRONTOTEMPORAL dementia; DNA-binding proteins; PROGRANULIN; ENZYME-linked immunosorbent assay; CYCLOHEXIMIDE; MEMBRANE proteins; THERAPEUTICS
- Publication
Journal of Neurochemistry, 2013, Vol 126, Issue 6, p781
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/jnc.12329