Citations 3
TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia
Marks, Jordan D. , Ayuso, Virginia Estades, Carlomagno, Yari , Yue, Mei, Todd, Tiffany W. , Hao, Ying , Li, Ziyi , McEachin, Zachary T. , Shantaraman, Anantharaman , Daughrity, Lillian M. , Jansen‐West, Karen , Calliari, Anna , Bejarano, Jesús González , DeTure, Michael , Rawlinson, Bailey, Castanedes‐Casey, Monica , Lilley, Meredith T. , Donahue, Megan , Jawahar, Vidhya Maheswari, Petersen, Ronald C. , Oskarsson, Björn , Graff‐Radford, Neill R. , Josephs, Keith A. , Seyfried, Nicholas T., Ward, Michael E. , Zhang, Yong‐Jie , Prudencio, Mercedes , Petrucelli, Leonard , Cook, Casey , Duong, Duc M , Daughrity, Lillian M , Jansen-West, Karen R , Shao, Wei , Calliari, Anna , Bejarano, Jesus Gonzalez , DeTure, Michael , Castanedes-Casey, Monica , Lilley, Meredith T , Donahue, Megan H , Boeve, Brad , Petersen, Ronald C , Knopman, David S. , Oskarsson, Björn , Wszolek, Z.K. , Dickson, Dennis W , Josephs, Keith A , Qi, Yue A , Seyfried, Nicholas T , Ward, Michael E , Zhang, Yong-Jie , Prudencio, Mercedes , Petrucelli, Leonard , Cook, Casey N , Li, Ziyi , Shantaraman, Anantharaman , Estades Ayuso, Virginia , Shao, Wei , Bharathi, Vidhya , Boeve, Bradley F. , Knopman, David S. , Wszołek, Zbigniew K. , Dickson, Dennis W. , Qi, Yue , Seyfried, Nicholas T.
Science Translational Medicine | January 17, 2024 | Volume: 16 | Issue: 730 | Pages: No page available
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.
Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration
Shao, Wei , Todd, Tiffany W. , Wu, Yanwei , Jones, Caroline Y. , Tong, Jimei, Jansen‐West, Karen , Daughrity, Lillian M. , Park, Jinyoung , Koike, Yuka , Kurti, Aishe, Yue, Mei, Castanedes‐Casey, Monica , Rosso, Giulia del, Dunmore, Judith A. , Alepuz, Desiree Zanetti , Oskarsson, Björn , Cook, Casey , Prudencio, Mercedes , Fryer, John Denis , Zhang, Yong‐Jie , Petrucelli, Leonard , Del Rosso, Giulia, Zanetti Alepuz, Desiree, Dickson, Dennis W , Cook, Casey N , Prudencio, Mercedes , Gendron, Tania F , Zhang, Yong-Jie , Petrucelli, Leonard , Oskarsson, Björn , Shao, Wei , Koike, Yuka , Dickson, Dennis W. , Gendron, Tania F.
Science | October 6, 2022 | Volume: 378 | Issue: 6615 | Pages: 94-99
Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 ( TBK1 ) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg 228 →His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72 , TBK1 , and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.
C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy
Cook, Casey , Wu, Yanwei , Odeh, Hana M. , Gendron, Tania F. , Jansen‐West, Karen , Rosso, Giulia del, Yue, Mei, Jiang, Peizhou , Gomes, Edward, Tong, Jimei, Daughrity, Lillian M. , Avendano, Nicole M., Castanedes‐Casey, Monica , Shao, Wei , Oskarsson, Björn , Tomassy, Giulio Srubek, McCampbell, Alexander , Rigo, Frank , Zhang, Yong‐Jie , Petrucelli, Leonard , Cook, Casey N , Del Rosso, Giulia, Dickson, Dennis W , Shorter, James , Zhang, Yong-Jie , Petrucelli, Leonard , Oskarsson, Björn , Gendron, Tania F , Shao, Wei , Dickson, Dennis W. , Shorter, James
Science Translational Medicine | September 2, 2020 | Volume: 12 | Issue: 559 | Pages: No page available
G 4 C 2 repeat–derived poly(GR) plays a key role in mediating TDP-43 mislocalization and aggregation in vitro and in vivo.