Role of VCP inhibition in the autophagic processing of misfolded rhodopsin

01/11/2019 to 31/10/2020

Autophagy is a major intracytoplasmic protein degradation pathway whereby cytoplasmic contents are delivered to the lysosome for degradation. Autophagy dysregulation contributes to the pathogenesis of neurodegenerative diseases and its homeostasis is considered to foster the life-span extension of cells. The presence of intraneuronal aggregates of misfolded proteins, substrates for autophagic degradation, is the major pathological phenotype in several neurodegenerative diseases, including retinitis pigmentosa (RP) and age-related macular degeneration.

Our focus is the understanding and restoration of proteostasis in RP leading to affect proper folding of rhodopsin (Rho) followed by the progressive loss of photoreceptors (PRs). ER-associated degradation (ERAD) and autophagy are two interconnected routes for the degradation of misfolded proteins. We have discovered that modulation of the proteasomal degradation rescues PRs in rodent models for RD as well as in Drosophila.

Based on own preliminary as well as previously published data, we have reasons to believe that the combined activity of both, ERAD and autophagy, is responsible, at least in part, for the clearance of Rho, once it fails to pass molecular quality control for proteasomal degradation. We, therefore, aim to study the role of autophagy in RP and determine the impact of VCP inhibition on the autophagy machinery. This will enable us to better understand the mechanisms of PR protection with respect to the strong therapeutic efficacy of proteasomal targeting inhibition towards rational therapy development for RD.