期刊
JOURNAL OF NEUROCHEMISTRY
卷 126, 期 6, 页码 781-791出版社
WILEY-BLACKWELL
DOI: 10.1111/jnc.12329
关键词
frontotemporal dementia; glycosylation; progranulin; TMEM106B
资金
- Consortium for Frontotemporal Dementia Research (CFR)
- Mayo Foundation
- NIH [R01 NS065782, R01 AG026251, P50 AG016574, R01AG032990, P50AG016574]
- Association for Frontotemporal Degeneration (AFTD) Postdoctoral Fellowship
- CIHR Clinical Genetics Investigatorship
- CIHR [179009]
- PARF [C06-01]
- Fondazione CARIPLO [2009-2633]
- Ricerca Corrente, Italian Ministry of Health
- Centres of Excellence in Neurodegeneration [COEN015]
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 TMEM106Bvariants with FTLD-TDP in anew 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.
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