Aging is the major risk factor for development of neurodegenerative diseases (NDs) development. The process of aging is not only affected by stochastic events and environmental insults, but also by metabolic and genetic alterations. One example for a genetic regulator of aging is the insulin/insulin-like growth factor 1 (IGF-1) signalling (IIS) pathway. Downregulation of this pathway extends lifespan and promotes protein homeostasis (proteostasis) in various organisms. In Caenorhabditis elegans (C. elegans), IIS pathway reduction can alter the organismal metabolism, while dietary restriction (DR) extends the worms lifespan via the IIS. In Alzheimer’s disease (AD) mouse models, downregulation of the IGF1 signalling reduces the levels of Aβ levels in the brain and protect animals from AD-like phenotypes. In this project, we wanted to explore novel genes regulated by the IIS, that promote proteostasis through metabolic alteration. We discovered that the knockdown (KD) of the C. elegans gene Y50D4B.2 protects the animal from chronic proteotoxic stress. We further demonstrate that the KD of Y50D4B.2 alters cellular metabolism, promoting proteostasis through key IIS and DR transcription factors. Y50D4B.2 was found expressed mainly in neurons, suggesting its involvement in proteostasis-promoting inter-tissue communication. With this project, we aim to broaden our understanding of the basic mechanisms which link metabolism and proteostasis, allowing future therapeutic approaches against NDs.

Supervisor: Prof. Ehud Cohen