fus transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration付家转基因老鼠开发肌萎缩性脊髓侧索硬化症的表型和额颞叶大叶性变性.pdfVIP

FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration 1. 1. 1 2 3 1 1 Cao Huang , Hongxia Zhou *, Jianbin Tong , Han Chen , Yong-Jian Liu , Dian Wang , Xiaotao Wei , Xu-Gang Xia1* 1 Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America, 2 Center for Biotechnology, University of Nebraska–Lincoln, Lincoln, Nebraska, United States of America, 3 Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America Abstract Fused in Sarcoma (FUS) proteinopathy is a feature of frontotemporal lobar dementia (FTLD), and mutation of the fus gene segregates with FTLD and amyotrophic lateral sclerosis (ALS). To study the consequences of mutation in the fus gene, we created transgenic rats expressing the human fus gene with or without mutation. Overexpression of a mutant (R521C substitution), but not normal, human FUS induced progressive paralysis resembling ALS. Mutant FUS transgenic rats developed progressive paralysis secondary to degeneration of motor axons and displayed a substantial loss of neurons in the cortex and hippocampus. This neuronal loss was accompanied by ubiquitin aggregation and glial reaction. While transgenic rats that overexpressed the wild-type human FUS were asymptomatic at young ages, they showed a deficit in spatial learning and memory and a significant loss of cortical and hippocampal neurons at advanced ages. These results suggest that mutant FUS is more toxic to neurons than normal FUS and that increased expression of normal FUS is sufficient to induce neu