Grant: Project Grant

Increased lifespan in developed countries has led to a higher prevalence of diverse age-related neurodegenerative disorders. They are known as "protein conformational diseases" because the common cause of the neuronal malfunction is the toxic deposit of misfolded proteins resulting from the loss of protein homeostasis. Neurodegenerative diseases are progressive disorders whose initiation involves the loss of interneuronal connections. As of today, we still lack efficient treatments to prevent the progression of these diseases. Induction of expression of a group of proteins, the Heat Shock Proteins (HSPs), has been considered a therapeutic approach to treating age-related neurodegenerative conditions. HSPs hold misfolded proteins and refold them, preventing their aggregation. However, it is unknown how HSPs are directed to the sites of interneuronal connections. This project aims to uncover the molecular mechanisms that mediate the localization of HSPs at neuronal connections. We will combine cutting-edge single-molecule fluorescence microscopy tools with molecular approaches to answer this essential question in mouse primary neuronal cultures undergoing pathophysiological stresses. We expect this work to answer a long-standing question on the maintenance of functional neuronal connections and pave the way to develop therapies that stop the progression of age-related neurodegenerative diseases.