Disruption of peripheral circadian timekeeping in a mouse model of Huntington's disease and its restoration by temporally scheduled feeding.
Behavioral circadian rhythms disintegrate progressively in the R6/2 mouse model of Huntington's disease (HD), recapitulating the sleep-wake disturbance seen in HD patients. Here we show that disturbances in circadian pacemaking are not restricted to the brain, but also encompass peripheral metabolic pathways in R6/2 mice. Notably, circadian rhythms of clock-driven genes that are key metabolic outputs in the liver are abolished in vivo. This deficiency is accompanied by arrhythmic expression of the clock genes Cry1 and Dbp, and a phase-advanced Per2 cycle. Compromised circadian metabolic cycles are not, however, a consequence of deficient pacemaking intrinsic to the liver, because when cultured in vitro, R6/2 liver slices exhibit self-sustained circadian bioluminescence rhythms. We therefore propose that compromised metabolic cycles arise from an internal desynchronization secondary to altered feeding patterns and impaired circadian signaling from the central pacemaker of the suprachiasmatic nucleus (SCN). Importantly, the SCN-independent food-entrainable oscillator remains intact in R6/2 mice and, when invoked, can restore daily behavioral cycles and reverse some of the metabolic abnormalities seen in the liver. Disturbances of metabolism have long been thought to be an important feature of HD. Uncoupling liver metabolism from circadian drives will reduce metabolic efficiency and cause imbalances in metabolites known to be deleterious to brain function. Thus, even subtle imbalances in liver function may exacerbate symptoms of HD, where neurological function is already compromised.
Maywood
Elizabeth S
ES
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, United Kingdom.
Fraenkel
Eloise
E
McAllister
Catherine J
CJ
Wood
Nigel
N
Reddy
Akhilesh B
AB
Hastings
Michael H
MH
Morton
A Jennifer
AJ
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005247:Feeding Behavior / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000534:rehabilitation*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D009924:Organ Culture Techniques; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger