1. Department of Neuroscience, Mayo Clinic, , Jacksonville, Florida, USA;2. NeuroBioGen Lab‐Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, , Brescia, Italy;3. Proteomics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, , Brescia, Italy;4. Division of Neurology, University of British Columbia, , Vancouver, British Columbia, Canada;5. Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, , London, Ontario, Canada;6. Department of Neurology, Mayo Clinic, , Rochester, Minnesota, USA;7. Department of Neurology, Mayo Clinic, , Jacksonville, Florida, USA
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.
