Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
11031668 | Neurobiology of Aging | 2018 | 45 Pages |
Abstract
Mutations in fused in sarcoma (Fus) cause familial amyotrophic lateral sclerosis (ALS) and occasionally frontotemporal dementia. Here we report the establishment and characterization of a novel knockin (KI) rat model expressing a Fus point mutation (R521C) via CRISPR/Cas9. The mutant animals developed adult-onset learning and memory behavioral deficits, with reduced spine density in hippocampal neurons. Remarkably, sleep-wake cycle and circadian abnormalities preceded the onset of cognitive deficit. RNA-seq study further demonstrated altered expression of some key sleep and circadian regulators, such as orexin/hypocretin receptor type 2 and casein kinase 1 epsilon, in the mutant rats. Therefore, we have established a rodent model expressing physiological level of a pathogenic mutant FUS, and we found cognitive impairment as a main behavioral deficit at mid age. Furthermore, we have revealed a new role of FUS in sleep and circadian regulation and demonstrated that functional change in FUS could cause sleep-wake and circadian disturbance as early symptoms.
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Biochemistry, Genetics and Molecular Biology
Ageing
Authors
Tao Zhang, Xin Jiang, Min Xu, Haifang Wang, Xiao Sang, Meiling Qin, Puhua Bao, Ruiqi Wang, Chenchen Zhang, Huiping Lu, Yuzhuo Li, Jin Ren, Hung-Chun Chang, Jun Yan, Qiang Sun, Jin Xu,