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Sleep and circadian abnormalities precede cognitive deficits in R521C FUS knockin rats
- Source :
- Neurobiology of aging. 72
- Publication Year :
- 2018
-
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.
- Subjects :
- 0301 basic medicine
Aging
Mutant
Hippocampal formation
Biology
Chronobiology Disorders
Rats, Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
Sleep Disorders, Circadian Rhythm
medicine
Animals
Cognitive Dysfunction
Circadian rhythm
Amyotrophic lateral sclerosis
Wakefulness
Cognitive deficit
Cells, Cultured
Behavior, Animal
Electromyography
General Neuroscience
Point mutation
Age Factors
Electroencephalography
medicine.disease
Embryo, Mammalian
Orexin
Rats
Disease Models, Animal
030104 developmental biology
RNA-Binding Protein FUS
Neurology (clinical)
Geriatrics and Gerontology
medicine.symptom
Rats, Transgenic
Sleep
Neuroscience
030217 neurology & neurosurgery
Developmental Biology
Frontotemporal dementia
Subjects
Details
- ISSN :
- 15581497
- Volume :
- 72
- Database :
- OpenAIRE
- Journal :
- Neurobiology of aging
- Accession number :
- edsair.doi.dedup.....1deaa8cf27a71115596be2ac80a9c8b2