Citations 3
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.
Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity
Zhang, Yong‐Jie , Guo, Lin , Gonzales, Patrick , Gendron, Tania F. , Wu, Yanwei , Jansen‐West, Karen , O’Raw, Aliesha D. , Pickles, Sarah , Prudencio, Mercedes , Carlomagno, Yari , Gachechiladze, Mariam A. , Tian, Ruilin , Chew, Jeannie , DeTure, Michael , Lin, Wen-Lang, Tong, Jimei, Daughrity, Lillian M. , Yue, Mei, Song, Yuping , Andersen, Jonathan W. , Castanedes‐Casey, Monica , Kurti, Aishe, Antognetti, Giovanna, McCampbell, Alexander , Rademakers, Rosa , Oskarsson, Björn , Kampmann, Martin , Ward, Michael E. , Fryer, John Denis , Link, Christopher D. , Shorter, James , Petrucelli, Leonard , Gonzales, Patrick K , Pickles, Sarah R , Chew, Jeannie , DeTure, Michael , Daughrity, Lillian M , Castanedes-Casey, Monica , McCampbell, Alexander , Rademakers, Rosa , Oskarsson, Björn , Dickson, Dennis W , Kampmann, Martin , Ward, Michael E , Shorter, James , Petrucelli, Leonard , Zhang, Yong-Jie , Prudencio, Mercedes , O'Raw, Aliesha , Gendron, Tania F , Guo, Lin , Ludwig, Connor , Datta, Abhishek, Dickson, Dennis W.
Science | February 15, 2019 | Volume: 363 | Issue: 6428 | Pages: No page available
How dipeptide repeats cause pathology A repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common known cause of two neurodegenerative diseases: frontotemporal dementia and amyotrophic lateral sclerosis. This expansion leads to the abnormal production of proteins of repeating dipeptides, but their contribution to disease pathogenesis remains unclear. Zhang et al. engineered a mouse model to study the consequences of one of these dipeptides—prolinearginine dipeptide repeat protein, poly(PR)—in the brain. They found that poly(PR) caused neuron loss as well as motor and memory impairments. These detrimental effects resulted from poly(PR)-induced perturbation of heterochromatin function, a tightly packed form of DNA that represses gene expression. Science , this issue p. eaav2606