Posterior Column Ataxia and Retinitis Pigmentosa: new pathogenetic insights from the study of mitochondria-associated membranes

The aim of this project is to identify the mechanism responsible for the degeneration of sensory neurons in Posterior Column Ataxia and Retinitis Pigmentosa (PCARP) and to identity a therapeutic target. PCARP is a rare genetic disease characterized by the progressive degeneration of sensory neurons and photoreceptor. The loss of these specific cell types leads to ataxia, inability to sense pain and progressive vision loss. The disease is due to mutations in a gene named Feline Leukemia Virus Subgroup C Receptor 1 (FLVCR1) gene. The gene encodes a protein that is involved in the export of heme. However, the reason why mutations in this gene cause PCARP is still unknown and a specific therapy for PCARP patients is lacking. Our unpublished research performed on fibroblasts derived from patients and healthy donor subjects showed that these cells are unable to produce energy, ATP. Moreover, we identify a strategy to correct the defect in patients-derived fibroblasts thus improving ATP production. Based on these promising results, we hypothesize that sensory neurons degeneration in PCARP may be due to defective energetic metabolism and therefore, strategies aimed at restoring cell bioenergetics are interesting for therapeutic purposes in PCARP. This project aims to validate these hypothesis in appropriate cellular model of PCARP. This project will focus on sensory neurons butwe envision important future implications of this study in the understanding of the mechanisms of photoreceptors degeneration in PCARP.