Sleep and circadian abnormalities precede cognitive deficits in R521C FUS knockin rats.
Neurobiol Aging
; 72: 159-170, 2018 12.
Article
in En
| MEDLINE
| ID: mdl-30273830
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sleep
/
Wakefulness
/
Behavior, Animal
/
Chronobiology Disorders
/
RNA-Binding Protein FUS
/
Cognitive Dysfunction
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Neurobiol Aging
Year:
2018
Document type:
Article
Affiliation country:
China
Country of publication:
Estados Unidos