TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia

• DOI: 10.1126/scitranslmed.adf9735
• Publication Date: 2024-01-17T18:58:38Z
• Authors: Jordan D. Marks; Virginia Estades ...; Yari Carlomagno; Mei Yue; Tiffany W. Todd; Ying Hao; Ziyi Li; Zachary T. McEachin; Anantharaman Shan...; Duc M. Duong; Lillian M. Daughrity; Karen Jansen-West; Wei Shao; Anna Calliari; Jesus Gonzalez Be...; Michael DeTure; Bailey Rawlinson; Monica Castanedes...; Meredith T. Lilley; Megan H. Donahue; Vidhya Maheswari ...; Bradley F. Boeve; Ronald C. Petersen; David S. Knopman; Björn Oskarsson; Neill R. Graff-Ra...; Zbigniew K. Wszolek; Dennis W. Dickson; Keith A. Josephs; Yue A. Qi; Nicholas T. Seyfried; Michael E. Ward; Yong-Jie Zhang; Mercedes Prudencio; Leonard Petrucelli; Casey N. Cook
• Keywords: Frontotemporal lobar degeneration

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence TMEM106B rs3173615 protective genotype was associated longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting slower disease course. The seminal discovery filaments derived from is common feature aging and, across range neurodegenerative disorders, suggests genetic variants could modulate and progression modulating aggregation. To explore this possibility assess pathological relevance accumulation, we generated new antibody targeting filament core sequence. Analysis samples revealed allele higher accumulation patients FTLD-TDP. In contrast, minimal deposition detected carriers allele. Although abundance monomeric full-length unchanged, exhibited increase dimeric TMEM106B. Increased also enhanced dysfunction, interactome data suggested role for impaired RNA transport, local translation, endolysosomal function Overall, these findings suggest prevention central mechanism by which haplotype reduces slows progression.