Disintegration of the sleep-wake cycle and circadian timing in Huntington's disease.
Sleep disturbances in neurological disorders have a devastating impact on patient and carer alike. However, their pathological origin is unknown. Here we show that patients with Huntington's disease (HD) have disrupted night-day activity patterns. This disruption was mirrored in a transgenic model of HD (R6/2 mice) in which daytime activity increased and nocturnal activity fell, eventually leading to the complete disintegration of circadian behavior. The behavioral disturbance was accompanied by marked disruption of expression of the circadian clock genes mPer2 and mBmal1 in the suprachiasmatic nuclei (SCN), the principal circadian pacemaker in the brain. The circadian peak of expression of mPer2 was prematurely truncated, and the mRNA levels of mBmal1 were attenuated and failed to exhibit a significant circadian oscillation. Circadian cycles of gene expression in the motor cortex and striatum, markers of behavioral activation in wild-type mice, were also suppressed in the R6/2 mice, providing a neural correlate of the disturbed activity cycles. Increased daytime activity was also associated with reduced SCN expression of prokineticin 2, a transcriptional target of mBmal1 encoding a neuropeptide that normally suppresses daytime activity in nocturnal mammals. Together, these molecular abnormalities could explain the pathophysiological changes in circadian behavior. We propose that circadian sleep disturbances are an important pathological feature of HD, that they arise from pathology within the SCN molecular oscillation, and that their treatment will bring appreciable benefits to HD patients.
Morton
A Jennifer
AJ
Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom. ajm41@cam.ac.uk
Wood
Nigel I
NI
Hastings
Michael H
MH
Hurelbrink
Carrie
C
Barker
Roger A
RA
Maywood
Elizabeth S
ES
D000328:Adult; D000368:Aged; D000818:Animals; D021081:Chronobiology Disorders / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D020920:Dyssomnias / Q000209:etiology* / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006816:Huntington Disease / Q000150:complications* / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology; D020178:Sleep Disorders, Circadian Rhythm / Q000209:etiology; D013493:Suprachiasmatic Nucleus / Q000378:metabolism / Q000503:physiopathology*