SIRWOLFPHAGY

WWolfram syndrome (WS) is a rare neurodegenerative disease combining optic atrophy, deafness and diabetes mellitus. There is no treatment of WS and patients die around 35 y.o. from respiratory or swallowing failure. Recently, we demonstrated that the communication between endoplasmic reticulum (ER) and mitochondria that are tightly connected via the so-called MAM site (for mitochondria-associated membrane) was impaired in WS, leading to mitochondrial deficiency. Our data indeed suggested that it is possible to restore the anomalies by targeting ER-mitochondria function. The sigma-1 receptor (S1R), a transmembrane protein highly enriched in MAMs, interacts with several partners involved in ER-mitochondria Ca2+ transfer, thus enhancing Ca2+ efflux from the ER into the mitochondria and improving mitochondrial function. We used the S1R agonist PRE-084 to demonstrate that MAM functional enhancement could be used to restore WS alterations. The PRE-084 treatment restored Ca2+ transfer and mitochondrial respiration in vitro, corrected the associated impaired autophagy and mitophagy and was able to alleviate the behavioral symptoms observed in two genetic animal models of the disease. The unexpected altered auto/mitophagy prompted us to identify binding partner of WFS1. We isolated several partners involved in the regulation of the autophagic process. The project aim is to decipher molecular mechanisms by which WFS1 and S1R regulate neuronal autophagy. Using models deficient for WFS1 (NCS34 cells, WFS1deltaexon8 mice) and S1R (LUHMES cells, S1RKO mice), we will confirm the interaction of WFS1 with its preys and evaluate the impact of WFS1 and S1R loss of function on the effects of the preys. In addition, we will determine the role of the proteins on autophagosome formation and transport in neurons. Finally, we will activate S1R with a photoswitchable agonist in different localization of the neuron to determine the precise mechanism of action.