The Effect of Cicadian Therapies in Models of Neurodegenerative Disease
Huntington’s Disease (HD) is an autosomal dominant disorder caused by excessive CAG repeats in the gene encoding the huntingtin protein which leads to progressive neurodegeneration that inflicts cognitive, psychiatric, cardiovascular and motor dysfunction. There is currently no treatment to prevent or delay the course of the disease. Neuronal loss in the striatum is thought to be responsible for the abnormal motor control present in HD patients, though the pathophysiology behind the non-motor symptoms is still unclear. Disturbances in sleep-wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and excessive fatigue, and these disruptions are recapitulated in mouse models. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early interventions that improve circadian rhythmicity could benefit HD symptoms and delay disease progression.
Evidence of altered histaminergic signaling in HD patients suggests that this pathway may contribute to disrupted rhythms in arousal. Utilizing the Q175 mouse model of HD, we demonstrated that nightly treatment with a histamine-3 receptor antagonist/inverse agonist improved several behavioral measures of HD including strengthening activity rhythms, cognitive performance, and mood, as well as reducing inappropriate activity during the normal sleep time. Our findings suggest that drugs targeting the histamine-3 receptor system may be beneficial as cognitive enhancers in the management of HD.
One of the most powerful regulators of the circadian system is the daily feed/fast cycle, and in two separate studies we found that three months of time-restricted feeding (6-hours of feeding in the middle of the active phase followed by 18-hours fasting) improved the sleep/wake cycle, motor symptoms, and autonomic function in both the Q175 and BACHD mouse models.
Finally, we sought to determine whether a ketogenic diet was sufficient to impart motor performance and sleep/wake rhythm benefits in BACHD mice similar to those observed under TRF. We found that the ketogenic diet improves circadian dysfunction as well as motor symptoms in the BACHD mouse model.
Altogether, these studies support the hypothesis that early interventions that improve sleep/wake timing and circadian rhythmicity can ameliorate a range of symptoms of HD and related neurodegenerative disorders.