Do Disruptions in the Circadian Timing System Contribute to Autonomic Dysfunction in Huntington's Disease?

Huntington's disease (HD) patients suffer from a progressive neurodegenerative disorder that inflicts both motor and non-motor symptoms. HD is caused by a CAG repeat expansion within the first exon of the huntingtin (HTT) gene that produces a polyglutamine repeat that leads to protein misfolding, soluble aggregates, and inclusion bodies detected throughout the body. Both clinical and preclinical research indicate that cardiovascular dysfunction should be considered a core symptom in at least a subset of HD patients. There is strong evidence for dysautonomia (dysfunctional autonomic nervous system, ANS) in HD patients that can be detected early in the disease progression. The temporal patterning of ANS function is controlled by the circadian timing system based in the anterior hypothalamus. Patients with neurodegenerative diseases including HD exhibit disrupted sleep/wake cycle and, in preclinical models, there is compelling evidence that the circadian timing system is compromised early in the disease process. Here we review data from preclinical models of HD that explore the intersection between disruption of circadian rhythms and dysautonomia. This work will lead to new therapeutic strategies and standards of care for HD and other neurodegenerative diseases.