Grant: Project Grant

Neuropeptides are small signaling proteins that modulate brain functions, including emotion and cognition. Neuropeptides are frequently downregulated in brain disorders, from depression to Alzheimer's disease. We now show that more than half of the neuropeptides are also reduced with age. Understanding why these signaling molecules are selectively affected across brain conditions has implications for maintaining brain health and for treating brain-related disorders. Inspired by mechanisms affecting signaling proteins in organ diseases (insulin in diabetes) or misfolded proteins in neurodegenerative diseases, we began investigating the common cellular machinery that mediates the synthesis, processing and quality control of neuropeptides. Using somatostatin and BDNF as two prototypical neuropeptides negatively affected by age and brain disorders, we show that their sustained induction negatively affects this cellular machinery, leading to aggregation of proteins in the brain and to behavioural symptoms related to mood and cognition. We also show that blocking these disease-inducing events has therapeutic effects in rodent models. These results led us to hypothesize that sustained demand on small signaling proteins, as during stress and diseases, or reduced capacity to process them, as during aging, can induce pathologies associated with brain disorders. We also hypothesize that protecting the cellular machinery responsible for their production and quality control may block these disease-inducing events. Using multiple biological approaches across domains of research in rodents, we will investigate which small signaling proteins are prone to induce these cellular pathologies and by what mechanisms. The goals are to characterize a novel mechanism of brain disorders and to promote protein homeostasis and quality control as a universal mechanism relevant to a broad range of organ and brain diseases.