Treatment with ROS detoxifying metal nanoclusters alleviates the progressive functional decline in a mouse model of Friedreich's Ataxia

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease characterized by preogressive muscle weakness and locomotor deficits, degeneration of large sensory neurons in the dorsal root ganglia (DRGs), cardiomyopaties, diabetes mellitus and skeletal deformities. and brain, skeletal muscle and cardiac defects. The disease is caused by reduced expression of the mitochondrial protein frataxin due to an intronic GAA-repeat expansion in the FXN gene. Altered mitochondrial iron metabolism and turnover result in chronic excess of reactive oxygen species (ROS), hypersensitivity to ROS and consequent oxidative stress and cell damage. While the full molecular pathogenesis is still being clarified, a scavenging or detoxification from ROS could reasonably lead to delayed progression and to alleviate the disease phenotype. Since no treatment for FRDA is currently approved and experimental therapies are still unsatisfactory, efforts in this direction are urgently needed. We have exploited a novel system of ROS scavenging/detoxification based on Au-nanoclusters (NC), injected intravenously in a mouse model of FRDA (YG8sR mouse). The Au-NCs injected animals show a significant improvement of motor function, including physical resistance and gait balance, an improved cardiac contractility and insulin-dependent control of glycemia. These effects were accompanied by long-term improved mitochondrial functions, improved antioxidant cell responses and reduced ROS-dependent DNA and lipid damage in the CNS and muscles. These results show the Au-NCs mediated phenotypic rescue of FRD in YG8sR mice and encourage further optimization of this approach in experimental therapy of FRDA