Assess the role of the mitochondrial-nuclear connection in modulating neuronal autophagy

Backround and R&D challenge: Friedreichs ataxia (FRDA), the most frequent inherited recessive ataxia, causes nervous system damage and movement problems, it is ascribed to severely defective expression of frataxin, a nuclear-encoded mitochondrial protein . Autophagy is not only the major pathway for recycle intracellular components but also a highly conserved form of cell death associated both with prevention and cause of neurodegenerative diseases in human. Autophagic features were found in degenerating tissues of conditional frataxin KO mice, but the role of autophagy in FRDA pathogenesis and treatment, has never been investigated and is one of our main research focus. Based on its well-characterized nervous system, C. elegans represents a suitable mode l organism to study neurodegenerative diseases of genetic origin and to screen for neurotrophic drugs. We found that suppresssing the C. elegans frataxin homolog (frh-1) increases lifespan through autophagy induction in a p53 dependent manner (Schiavi A et al, Manuscript in preparation). Objectives and methods: With this proposal we will investigate how frataxin suppression induces autophagy and if this is specifically induced in the nervous system. Autophagy is regulated by different intracellular mech anisms. Using different knock-out strains and RNAi constructs against genes involved in autophagy together with our frh-1 RNAi we will address which branch of autophagy is altered in response to frataxin suppression. We will also investigate if specific m itochondrial parameters and DNA-damage response (DDR) genes are required to modulate frataxin suppression induction of autophagy. This project can help to understand the links between autophagic, mitochondrial and DDR pathways in FRDA (and possibly other neurodegenerative diseases) and could suggest novel possible treatments.