PATHOGENIC ROLE AND BIOCHEMICAL DYSFUNCTIONS ASSOCIATED WITH MTDNA ATPASE 6 GENE MUTATIONS

Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa (NARP) and certain forms of Leigh syndrome (MILS) are genetic diseases, they are maternally inherited, and they present severe clinical phenotypes. The two diseases are caused by a structural impairment of the mitochondrial DNA, resulting in the synthesis of a cellular protein, ATP synthase, which is unable to use the nutrient metabolism energy. The result is the reduced availability of the highly energetic molecule, ATP, needed by the cells. The severity of the disease is proportionate to the amount of impaired DNA in the cell. Thus, in order of increasing severity, the disease can go from retinitis pigmentosa (visual defect), to ataxia, muscle weakness, cardiomyopathy, mental retardation, and finally to neurodegeneration. Moreover, due to the particular genome affected, the clinical expression of the defect worsens as patients grow older and they face an early death. At present, there is no available therapy for these patients. This research project aims to clarify the biochemical dysfunctions induced by the DNA impairment. This is essential in designing appropriate therapeutic approaches which can cure or at least reduce the rate of progression of the disease.