Circadian rhythm dysfunction occurs in both common and rare neurodegenerative diseases. This dysfunction manifests as sleep cycle mistiming, alterations in body temperature rhythms, and an increase in symptomatology during the early evening hours known as Sundown Syndrome. Disruption of circadian rhythm homeostasis has also been implicated in the etiology of neurodegenerative disease. Indeed, individuals exposed to a shifting schedule of sleep and activity, such as health care workers, are at a higher risk. Thus, a bidirectional relationship exists between the circadian system and neurodegeneration. At the heart of this crosstalk is the molecular circadian clock, which functions to regulate circadian rhythm homeostasis. Over the past decade, this connection has become a focal point of investigation as the molecular clock offers an attractive target to combat both neurodegenerative disease pathogenesis and circadian rhythm dysfunction, and a pivotal role for neuroinflammation and stress has been established. This review summarizes the contributions of molecular clock dysfunction to neurodegenerative disease etiology, as well as the mechanisms by which neurodegenerative diseases affect the molecular clock.
Over the past decades the molecular mechanisms responsible for circadian phenotypes of animals have been studied in increasing detail in mammals, some insects, and other invertebrates. Particular circadian proteins and their interactions are shared across evolutionary distant animals resulting in a hypothesis for the canonical circadian clock of animals. As the number of species for which the circadian clockwork has been described increases, the circadian clock in animals driving cyclical phenotypes becomes less similar. Our focus in this review is to develop and synthesize the current literature to better understand the antiquity and evolution of the animal circadian clockwork. Here, we provide an updated understanding of circadian clock evolution in animals, largely through the lens of conserved genes characterized in the circadian clock identified in bilaterian species. These comparisons reveal extensive variation within the likely composition of the core clock mechanism, including losses of many genes, and that the ancestral clock of animals does not equate to the bilaterian clock. Despite the loss of these core genes, these species retain circadian behaviors and physiology suggesting novel clocks have evolved repeatedly. Additionally, we highlight highly conserved cellular processes (e.g., cell division, nutrition) that intersect with the circadian clock. The conservation of these processes throughout the animal tree remains essentially unknown, but understanding their role in the evolution and maintenance of the circadian clock will provide important areas for future study.
Time-of-day effects have been noted in a wide variety of cognitive behavioral tests, and perturbation of the circadian system, either at the level of the master clock in the SCN or downstream, impairs hippocampus-dependent learning and memory. A number of kinases, including the serine-threonine casein kinase 1 (CK1) isoforms CK1δ/ε, regulate the timing of the circadian period through post-translational modification of clock proteins. Modulation of these circadian kinases presents a novel treatment direction for cognitive deficits through circadian modulation. Here, we tested the potential for PF-670462, a small molecule inhibitor of CK1δ/ε, to improve cognitive performance in C57BL/6J mice in an array of behavioral tests. Compared to vehicle-treated mice tested at the same time of the circadian day, mice treated with PF-670462 displayed better recall of contextual fear conditioning, made fewer working memory errors in the radial arm water maze, and trained more efficiently in the Morris Water Maze. These benefits were accompanied by increased expression of activity-regulated cytoskeleton-associated protein (Arc) in the amygdala in response to an acute learning paradigm. Our results suggest the potential utility of CK1δ/ε inhibition in improving time-of-day cognitive performance.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.