Abstract
Sleep and circadian disruptions are commonly reported by patients with neurodegenerative diseases, suggesting these may be an endophenotype of the disorders. Several mouse models of Huntington’s disease (HD) that recapitulate the disease progression and motor dysfunction of HD also exhibit sleep and circadian rhythm disruption. Of these, the strongest effects are observed in the transgenic models with multiple copies of mutant huntingtin gene. For developing treatments of the human disease, knock-in (KI) models offer advantages of genetic precision of the insertion and control of mutation copy number. Therefore, we assayed locomotor activity and immobility-defined sleep in a new model of HD with an expansion of the KI repeats (Q175). We found evidence for gene dose- and age-dependent circadian disruption in the behavior of the Q175 line. We did not see evidence for loss of cells or disruption of the molecular oscillator in the master pacemaker, the suprachiasmatic nucleus (SCN). The combination of the precise genetic targeting in the Q175 model and the observed sleep and circadian disruptions make it tractable to study the interaction of the underlying pathology of HD and the mechanisms by which the disruptions occur.
Highlights
Huntington’s disease (HD) is characterized by motor dysfunction and cognitive decline, and is caused by an autosomal dominant expansion of CAG repeats in the Huntingtin (HTT) gene [1]
In addition to the motor dysfunction, HD patients often present with non-motor symptoms that include cognitive dysfunction [4,5], affective disorders [6,7,8] and sleep and circadian rhythm disruptions [9,10,11,12], which can all precede the onset of chorea
A spontaneous expansion mutant that arose in this line of mice, with over 175 CAG repeats (Q175), has motor and cognitive deficits that have earlier onsets than the CAG140 line [24], and may exhibit sleep and circadian rhythm disruption that can be detected before WT rhythms decline
Summary
Huntington’s disease (HD) is characterized by motor dysfunction and cognitive decline, and is caused by an autosomal dominant expansion of CAG repeats in the Huntingtin (HTT) gene [1]. In addition to the motor dysfunction, HD patients often present with non-motor symptoms that include cognitive dysfunction [4,5], affective disorders [6,7,8] and sleep and circadian rhythm disruptions [9,10,11,12], which can all precede the onset of chorea. A spontaneous expansion mutant that arose in this line of mice, with over 175 CAG repeats (Q175), has motor and cognitive deficits that have earlier onsets than the CAG140 line [24], and may exhibit sleep and circadian rhythm disruption that can be detected before WT rhythms decline
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