Citations 2
C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits
Chew, Jeannie , Prudencio, Mercedes , Sasaguri, Hiroki , Zhang, Yong‐Jie , Castanedes‐Casey, Monica , Lee, Chris W. , Jansen‐West, Karen , Kurti, Aishe, Murray, Melissa E. , Bieniek, Kevin F. , Bauer, Peter , Whitelaw, Ena C., Rousseau, Linda , Stankowski, Jeannette N. , Stetler, Caroline, Daughrity, Lillian M. , Perkerson, Emilie A., Desaro, Pamela , Johnston, Amelia, Overstreet, Karen, Edbauer, Dieter , Rademakers, Rosa , Fryer, John Denis , Petrucelli, Leonard , Gendron, Tania F. , Castanedes-Casey, Monica, Jansen-West, Karen, Bauer, Peter O, Boylan, Kevin B, Fryer, John D., Boylan, Khrista , Dickson, Dennis W. , Zhang, Yong-Jie , Prudencio, Mercedes , Murray, Melissa E
Science | May 14, 2015 | Volume: 348 | Issue: 6239 | Pages: 1151-1154
A mouse model for ALS A G4C2 repeat expansion in C9ORF72 is known to be the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). However, a lack of animal models recapitulating key disease features has hindered efforts to understand and prevent c9FTD/ALS-related neurodegeneration. Until now. Chew et al. describe a mouse model that mimics both neuropathological and clinical phenotypes of c9FTD/ALS. Science , this issue p. 1151
Misregulation of human sortilin splicing leads to the generation of a nonfunctional progranulin receptor
Prudencio, Mercedes , Jansen‐West, Karen , Lee, Chris W. , Zhang, Yong‐Jie , Xu, Ya-Fei, Gass, Jennifer , Stuani, Cristiana , Stetler, Caroline, Rademakers, Rosa , Dickson, Dennis W. , Buratti, Emanuele , Petrucelli, Leonard , Gendron, Tania F. , Zhang, Yong-Jie , Prudencio, Mercedes , Dickson, Dennis W
Proceedings of the National Academy of Sciences | December 11, 2012 | Volume: 109 | Issue: 52 | Pages: 21510-21515
Sortilin 1 regulates the levels of brain progranulin (PGRN), a neurotrophic growth factor that, when deficient, is linked to cases of frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43)–positive inclusions (FTLD-TDP). We identified a specific splicing enhancer element that regulates the inclusion of a sortilin exon cassette (termed Ex17b) not normally present in the mature sortilin mRNA. This enhancer element is consistently present in sortilin RNA of mice and other species but absent in primates, which carry a premature stop codon within the Ex17b sequence. In the absence of TDP-43, which acts as a regulatory inhibitor, Ex17b is included in the sortilin mRNA. In humans, in contrast to mice, the inclusion of Ex17b in sortilin mRNA generates a truncated, nonfunctional, extracellularly released protein that binds to but does not internalize PGRN, essentially acting as a decoy receptor. Based on these results, we propose a potential mechanism linking misregulation of sortilin splicing with altered PGRN metabolism.