Alpha–lipoic acid supplementation improves pathological alterations in cellular models of Friedreich ataxia

Abstract

Abstract Background Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy, and an increased incidence of diabetes. The underlying pathophysiological mechanism of FRDA, driven by a significantly decreased expression of frataxin (FXN), involves increased oxidative stress, reduced activity of enzymes containing iron‑sulfur clusters, defective energy production, calcium dyshomeostasis, and impaired mitochondrial biogenesis, leading to mitochondrial dysfunction. Methods This study is aimed at evaluating the role of alpha-lipoic acid (ALA) in reversing the pathological alterations in fibroblasts and induced neurons derived from FRDA patients. Iron accumulation, lipid peroxidation, transcript and protein expression levels of frataxin, mitochondrial proteins, as well as mitochondrial bioenergetics were examined. Results Treatment with ALA was able to correct partially the pathological alterations in mutant fibroblasts. The optimal ALA concentration was dependent on the number of expanded GAA triplet repeats in the FXN gene. The positive effect of ALA was also confirmed in induced neurons derived from FRDA mutant fibroblasts. Our results also suggest that the positive effect of ALA was mediated by Peroxisome Proliferator-Activated Receptor Gamma activation. Conclusions Our results suggest that ALA treatment can increase the expression levels of frataxin and reverse the mutant phenotype in cellular models of FRDA.

Keywords

• Friedreich ataxia
• Frataxin
• Mitochondria
• Iron accumulation
• Fibroblasts
• Induced neurons