Sleep and neuronal energy management in neurodegeneration

Sleep is critical for brain function in many animals, and chronic disruptions in sleep patterns are strongly linked to the emergence of neurodegenerative diseases like Alzheimer’s and Parkinson’s. When animals sleep, neural
activity and brain metabolism change dramatically; however, we do not know what the molecular functions of
sleep are in the brain, nor do we know how these processes are linked to brain health. This proposal seeks to
understand how sleep regulates energy use in the brain, and focuses on a surprising link between how proteins and membranes are normally degraded, and how synaptic vesicles, the chemical currency of neuronal
computation, are formed. We will test the hypothesis that when the brain sleeps, energy usage is re-routed away from neuronal communication and toward protein and membrane remodeling, thereby allowing neurons and glia to restore key components needed on a daily basis for neural activity.

This hypothesis rests on the realization that the same molecular mechanism that powers protein degradation and membrane turnover also powers neuronal communication across synapses, the critical building block of neural computation. Proton gradients established by the same enzyme drive both of these processes energetically, and so these two pathways must compete for the same resources. Recent work has shown that both neural activity and degradation vary over the course of the day; we seek to understand how this daily regulation occurs. We take advantage of powerful genetic tools and brain imaging methods unique to the fruit fly to measure and perturb energy usage across the brain during sleep and wake. Prior work, including in our lab, has shown that disrupting these daily rhythms can decrease life span and accelerate neurodegeneration in many animals, including humans. Therefore, a molecular understand of how sleep promotes brain function will be valuable in developing strategies for improving resilience.