Cellular and molecular mechanisms underlying the interplay of proteostasis and sleep

• Applicants: Professor Dr. Henrik Bringmann; Professorin Dr. Janine Kirstein
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568324882

Sleep is essential and supports vital physiological processes of the brain and body. Sleep disorders are highly prevalent in modern societies, thus posing a massive unsolved health problem. However, despite its importance, it is not known how sleep becomes regenerative at the molecular level. Protein homeostasis, also known as proteostasis, is maintained by several carefully regulated mechanisms that control protein synthesis, folding, targeting and turnover. Cellular stress often leads to a breakdown of proteostasis and an increase of sleep and sleep in turn is essential to maintain proteostasis. Hence, there is a reciprocal relationship between sleep and proteostasis. How these two important biological processes are mechanistically linked is, however, not well understood. Central to the induction of sleep are sleep-active neurons that depolarize during sleep to inhibit neuronal wakefulness circuits. Sleep is evolutionarily conserved and can be studied across different animal models. Caenorhabditis elegans is advantageous for sleep research as it facilitates a molecular-mechanistic dissection of this process. We previously showed that sleep in C. elegans depends crucially on a single sleep-active neuron called RIS. Here, we provide preliminary evidence that RIS is required for proteostasis and that its loss leads to an increased aggregation of Ab42 and pathology in an Alzheimer’s disease model. Ab42 in turn leads to RIS over activation. However, it is not known how RIS and proteostasis and Ab42 aggregation are interlinked. The aim of this proposal is to understand how RIS controls neuronal proteostasis and how neuronal proteostasis in turn controls RIS activity. For this project, we will analyze how loss of proteostasis and Ab42 aggregation lead to RIS activation, and how RIS activity controls proteostasis via controlling gene expression and metabolic milieus required for proteostasis. This project will thus provide molecular mechanisms of how a sleep neuron controls neuronal proteostasis and how neuronal proteostasis controls sleep.

• DFG Programme: Research Grants