Molecular Crosstalk Between Circadian Rhythmicity and the Development of Neurodegenerative Disorders

Neurodegenerative disorders have been shown to exhibit substantial interconnectedness with circadian rhythmicity. Alzheimer’s patients exhibit high degradation of the SCN, the central endogenous circadian timekeeper, and Parkinson’s patients have highly disrupted peripheral clock gene expression. Disrupted sleep patterns are highly evident in patients with neurodegenerative diseases; fragmented sleep has been shown to affect tau-protein accumulation in Alzheimer’s patients, and REM behavioral disorder is observed in a significant amount of Parkinson’s patients. Although numerous studies exist analyzing the mechanisms of neurodegeneration and circadian rhythm function independently, molecular mechanisms establishing specific links between the two must be explored further. Thus, in this review, we explore the possible intersecting molecular mechanisms between circadian rhythm and neurodegeneration, with a particular focus on Parkinson’s disease. We provide evidence for potential influences of E3 ligase and PARP1 activity on neurodegenerative pathology. The cellular stress and subsequent DNA damage signaling imposed by hyperactivity of these multiple molecular systems in addition to aberrant circadian rhythmicity lead to extensive protein aggregation such as α-synuclein pre-formed fibrils (αSyn PFFs), suggesting a specific molecular pathway linking circadian rhythmicity, PARP1/E3 ligase activity, and Parkinson’s disease.