Friedreich ataxia (FRDA), the most common autosomal recessive
ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts,
cardiomyopathy, and increased incidence in 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 (ISC), defective energy production,
calcium dyshomeostasis, and impaired mitochondrial biogenesis, leading to
mitochondrial dysfunction. The
peroxisome proliferator-activated receptor gamma (PPARγ) is a
ligand-activated transcriptional factor playing a key role in mitochondrial function and biogenesis,
fatty acid storage, energy metabolism, and
antioxidant defence. It has been previously shown that the PPARγ/PPARγ coactivator 1 alpha (PGC-1α) pathway is dysregulated when there is
frataxin deficiency, thus contributing to FRDA pathogenesis and supporting the PPARγ pathway as a potential therapeutic target. Here we assess whether MIN-102 (INN:
leriglitazone), a novel brain penetrant and orally bioavailable PPARγ agonist with an improved profile for central nervous system (
CNS) diseases, rescues phenotypic features in cellular and animal models of FRDA. In
frataxin-deficient dorsal root ganglia (DRG) neurons,
leriglitazone increased
frataxin protein levels, reduced neurite degeneration and α-
fodrin cleavage mediated by
calpain and
caspase 3, and increased survival.
Leriglitazone also restored mitochondrial membrane potential and partially reversed decreased levels of mitochondrial Na+/Ca2+ exchanger (NCLX), resulting in an improvement of mitochondrial functions and
calcium homeostasis. In
frataxin-deficient primary neonatal cardiomyocytes,
leriglitazone prevented lipid droplet accumulation without increases in
frataxin levels. Furthermore,
leriglitazone improved motor function deficit in YG8sR mice, a FRDA mouse model. In agreement with the role of PPARγ in mitochondrial biogenesis,
leriglitazone significantly increased markers of mitochondrial biogenesis in FRDA patient cells. Overall, these results suggest that targeting the PPARγ pathway by
leriglitazone may provide an efficacious
therapy for FRDA increasing the mitochondrial function and biogenesis that could increase
frataxin levels in compromised
frataxin-deficient DRG neurons. Alternately,
leriglitazone improved the energy metabolism by increasing the
fatty acid β-oxidation in
frataxin-deficient cardiomyocytes without elevation of
frataxin levels. This could be linked to a lack of significant mitochondrial biogenesis and
cardiac hypertrophy. The results reinforced the different tissue requirement in FRDA and the pleiotropic effects of
leriglitazone that could be a promising
therapy for FRDA.