Sleep and circadian abnormalities precede cognitive deficits in R521C FUS knockin rats.
Neurobiology of Aging(2018)
摘要
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.
更多查看译文
关键词
FUS,ALS,FTD,Cognitive impairment,Sleep-wake cycle,Circadian rhythm
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要