Untangling the bidirectional relationship between the spread of pathological protein aggregates, sleep, and circadian clock disruption in neurodegenerative disease

PROJECT SUMMARY Over 7 million Americans currently suffer from a neurodegenerative disease (NDD), including Alzheimer’s disease and multiple system atrophy. In these disorders, intrinsically disordered proteins, including tau and α-synuclein (α-syn), misfold into a prion-like conformation capable of self-templating and spreading throughout the brain, causing progressive degeneration. Although age is the greatest known risk factor for the onset of NDDs, we urgently need to understand the mechanisms by which treatable risk factors contribute to disease, including sleep and circadian clock disruption. It is well established that sleep disruption impairs autophagy, whereas promoting autophagy via small molecules, such as rapamycin, delays disease onset in animal models of NDD. Given the growing literature identifying poor sleep quality and sleep disorders as both a preclinical sign and a symptom of NDDs, there is an increasing need to determine if protein misfolding leads to sleep and circadian desynchronization, if environmental circadian desynchronization (ECD) leads to protein misfolding, or if both occur in a positive feedback loop that is mediated via impaired autophagic activity. The long-term goal of our research is to understand the shared molecular mechanisms that contribute to the onset and progression of NDD. Our objective is to establish the mechanism(s) by which disrupted sleep and circadian timing contribute to the formation and spread of pathogenic tau and α-syn in the brain. We hypothesize that the effects of circadian clock disruption on tau and α-syn spreading in NDD are mediated by altered autophagic activity in the brain. Rather than a linear signaling pathway, we anticipate that ECD sits atop a positive feedback loop exacerbated by the presence of pathogenic protein in the brain. Our approach will investigate the bidirectional nature of this relationship. In Aim 1, we will investigate the effect of tau and α-syn propagation on sleep and circadian rhythms, and will determine if enhancing autophagy can slow these effects. In Aim 2, we will interrogate the effect of circadian clock manipulation on the onset and progression of NDD. We will also determine if ECD impairs autophagic activity to accelerate protein misfolding in the brain. While epidemiological and experimental studies have shown a clear interaction between circadian rhythms and NDDs, the nature of that relationship remains unclear. Successful completion of the proposed studies will determine if NDD drives circadian and sleep disruption, if ECD can drive NDD, and/or if the two exacerbate one another through a positive feedback loop. Notably, because this proposal draws on Dr. Woerman’s expertise in tau and α-syn misfolding in NDD and Dr. Karatsoreos’ expertise in circadian clock regulation of brain function, we are uniquely positioned as a multi-PI team to address this important question.