NAF Ataxia Research Studies Currently Underway

Natascia Venture, MD, PhD

University of Rome "Tor Vergata"
Experimental Medicine and Biochemical Science

Summary: This project is intended to provide insight into the molecular pathogenesis of Friedreich's Ataxia (FRDA), the most common inherited ataxia. FRDA is caused by the defective expression of the I FXN (FRDA, X25) gene, which leads to impaired expression of the encoded protein, frataxin. We recently generated a new powerful genetic tool to gain insight into the molecular pathogenesis of Friedreich's Ataxia (1). Lowering C.elegans frataxin homologue by RNAi, unexpectedly, increases nematode life span. In C.elegans, nevertheless, this is consistent with inactivation or reduction of other proteins involved in mitochondrial metabolism.

Worms with low level of frataxin are smaller, paler, have lower brood size and affected sensitivity to oxidative stress compare to control RNAi fed worm. Since most of the pathways so far described in C.elegans are very well conserved in humans, our provocative finding suggest new appealing function for frataxin in pathways controlling cell growth, metabolism, aging and the stress response. Different hypotheses can be formulated with the purpose of uncovering a role for frataxin in these important biological processes. In the nematode C. elegans, mutations that impact on life span belong mostly to the dauer-specifying insulin/IGF-1-like pathway and to proteins affecting mitochondrial metabolis. In both cases though, increased longevity can be ascribed to alterations in energy metabolic pathways, eventually resulting in increased resistance Ito stress. Understanding how C.elegans copes, and actually lives longer, with decreased frataxin could then shed lights on specific signal transduction pathways regulated frataxin.

We propose a model in which lowering frataxin affect mitochondrial metabolism and increase free radical production within a certain level that early in life may still induce stress response pathways and alter specific genes to maintain energy metabolism and rescue cell viability. Once beyond the threshold, free radical may induce an oxidative damage no longer tolerated from cells, which will eventually degenerate. The early induction of protective pathways would account and be sufficient to prolong C.elegans life-span. More importantly, the same pathways, activated early in life in FRDA cells, will rescue cell degeneration if supported with specific therapy before cell physiology is completely dismantled. The general aim of this project is then to shed light on premature signal transduction pathways affected by frataxin deficiency, which might be difficult to be recognized once the pathology is established. This will suggest new specific therapeutic strategies to prevent the diseases progression.