TY - JOUR
T1 - TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia
AU - Marks, Jordan D.
AU - Ayuso, Virginia Estades
AU - Carlomagno, Yari
AU - Yue, Mei
AU - Todd, Tiffany W.
AU - Hao, Ying
AU - Li, Ziyi
AU - McEachin, Zachary T.
AU - Shantaraman, Anantharaman
AU - Duong, Duc M.
AU - Daughrity, Lillian M.
AU - Jansen-West, Karen
AU - Shao, Wei
AU - Calliari, Anna
AU - Bejarano, Jesus Gonzalez
AU - DeTure, Michael
AU - Rawlinson, Bailey
AU - Casey, Monica Castanedes
AU - Lilley, Meredith T.
AU - Donahue, Megan H.
AU - Jawahar, Vidhya Maheswari
AU - Boeve, Bradley F.
AU - Petersen, Ronald C.
AU - Knopman, David S.
AU - Oskarsson, Björn
AU - Graff-Radford, Neill R.
AU - Wszolek, Zbigniew K.
AU - Dickson, Dennis W.
AU - Josephs, Keith A.
AU - Qi, Yue A.
AU - Seyfried, Nicholas T.
AU - Ward, Michael E.
AU - Zhang, Yong Jie
AU - Prudencio, Mercedes
AU - Petrucelli, Leonard
AU - Cook, Casey N.
N1 - Publisher Copyright:
© 2024 American Association for the Advancement of Science. All rights reserved.
PY - 2024/1/17
Y1 - 2024/1/17
N2 - 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 of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.
AB - 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 of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.
UR - http://www.scopus.com/inward/record.url?scp=85182784203&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85182784203&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adf9735
DO - 10.1126/scitranslmed.adf9735
M3 - Article
C2 - 38232138
AN - SCOPUS:85182784203
SN - 1946-6234
VL - 16
JO - Science translational medicine
JF - Science translational medicine
IS - 730
M1 - eadf9735
ER -