ClockNews #18: Orexin in Huntington's Disease
One of the distressing symptoms of progressive neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases is the severe disruption of sleep patterns, which leads to anxiety and distress in both patients and their caregivers. Two recent papers now shed light on the cellular and molecular mechanisms of sleep disruption in Huntington's disease (HD).
Petersen et al. find that HD patients and R6/2 mice (which mimic many of the features of human HD) exhibit progressive loss of brain neurons in the hypothalamus-- a key regulator of many different processes, including sleep. The hypothalamic neurons that die in HD patients and mice
produce the neuropeptide orexin, loss of which has been implicated in narcolepsy. Decreasing amounts of orexin in the cerebrospinal fluid of HD patients could thus be used as a marker of HD progression.
Orexin neurons in the hypothalamus also innervate the suprachiasmatic nucleus, which
drives circadian sleep/ wake cycles by regulating the transcription of several
key "clock" genes. Morton et al. report that progressive disruption of circadian
behavior in R6/2 mice is accompanied by marked alterations in the expression of
the mPer2 and mBmal1 clock genes. These findings help to explain why HD patients
suffer from markedly increased daytime sleepiness and night wakefulness, and
hopefully will contribute to better management of these distressing symptoms.
Hum. Mol. Genet. 14, 39 (2005); J. Neurosci. 25, 157 (2005).