| Literature DB >> 26998601 |
Yong-Jie Zhang1, Tania F Gendron1, Jonathan C Grima2,3,4, Hiroki Sasaguri1, Karen Jansen-West1, Ya-Fei Xu1, Rebecca B Katzman1, Jennifer Gass1, Melissa E Murray1, Mitsuru Shinohara1, Wen-Lang Lin1, Aliesha Garrett1, Jeannette N Stankowski1, Lillian Daughrity1, Jimei Tong1, Emilie A Perkerson1, Mei Yue1, Jeannie Chew1,5, Monica Castanedes-Casey1, Aishe Kurti1, Zizhao S Wang1, Amanda M Liesinger1, Jeremy D Baker6, Jie Jiang7, Clotilde Lagier-Tourenne8, Dieter Edbauer9,10,11, Don W Cleveland7,12, Rosa Rademakers1, Kevin B Boylan13, Guojun Bu1, Christopher D Link14, Chad A Dickey6, Jeffrey D Rothstein2,3,4, Dennis W Dickson1, John D Fryer1,5, Leonard Petrucelli1.
Abstract
Neuronal inclusions of poly(GA), a protein unconventionally translated from G4C2 repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.Entities:
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Year: 2016 PMID： 26998601 PMCID： PMC5138863 DOI： 10.1038/nn.4272
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 24.884