Oxidative damage compromises energy metabolism in the axonal degeneration mouse model of X-Adrenoleukodystrophy

Abstract

Aims: Chronic metabolic impairment and oxidative stress are associated with the pathogenesis of axonal dysfunction in a growing number of neurodegenerative conditions. To investigate the intertwining of both noxious factors, we have chosen the mouse model of adrenoleukodystrophy (X-ALD), which exhibits axonal degeneration in spinal cords and motor disability. The disease is caused by loss of function of the ABCD1 transporter, involved in the import and degradation of very long-chain fatty acids (VLCFA) in peroxisomes. Oxidative stress due to VLCFA excess appears early in the neurodegenerative cascade. Results: In this study, we demonstrate by redox proteomics that oxidative damage to proteins specifically affects five key enzymes of glycolysis and TCA (Tricarboxylic acid) cycle in spinal cords of Abcd1− mice and pyruvate kinase in human X-ALD fibroblasts. We also show that NADH and ATP levels are significantly diminished in these samples, together with decrease of pyruvate kinase activities and GSH levels, and increase of NADPH. Innovation: Treating Abcd1− mice with the antioxidants N-acetylcysteine and α-lipoic acid (LA) prevents protein oxidation; preserves NADH, NADPH, ATP, and GSH levels; and normalizes pyruvate kinase activity, which implies that oxidative stress provoked by VLCFA results in bioenergetic dysfunction, at a presymptomatic stage. Conclusion: Our results provide mechanistic insight into the beneficial effects of antioxidants and enhance the rationale for translation into clinical trials for X-adrenoleukodystrophy. Antioxid. Redox Signal. 15, 2095–2107.

This study was supported by grants from the European Commission [FP7-241622], the European Leukodystrophy Association [ELA2009-036C5; ELA2008-040C4], the Spanish Institute for Health Carlos III [FIS PI080991 and FIS PI051118], and the Autonomous Government of Catalonia [2009SGR85] to A.P. The CIBER de Enfermedades Raras is an initiative of the ISCIII. The study was developed under the COST action BM0604 [to A.P.]. J. L-E. was a fellow of the Department of Education, Universities, and Research of the Basque Regional Government [BFI07.126]. S.F. was a fellow of the European Leukodystrophy Association [ELA 2007-018F4], and J.G. was a fellow of the IDIBELL program of PhD-student fellowships. Work carried out at the Department of Experimental Medicine was supported in part by R+D grants from the Spanish Ministry of Science and Innovation [AGL2006-12433 and BFU2009-11879/BFI], the Spanish Ministry of Health [RD06/0013/0012 and PI081843], the Autonomous Government of Catalonia [2009SGR735], and COST B35 Action of the European Union. The authors are indebted to Professor Isabel Fabregat for scientific discussion.