Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: A paradigm for multifactorial neurodegenerative diseases?

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder expressed as four disease variants characterized by adrenal insufficiency and graded damage in the nervous system. X-ALD is caused by a loss of function of the peroxisomal ABCD1 fatty-acid transporter, resulting in the accumulation of very long chain fatty acids (VLCFA) in the organs and plasma, which have potentially toxic effects in CNS and adrenal glands. We have recently shown that treatment with a combination of antioxidants containing α-tocopherol, N-acetyl-cysteine and α-lipoic acid reversed oxidative damage and energetic failure, together with the axonal degeneration and locomotor impairment displayed by Abcd1 null mice, the animal model of X-ALD. This is the first direct demonstration that oxidative stress, which is a hallmark not only of X-ALD, but also of other neurodegenerative processes, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), contributes to axonal damage. The purpose of this review is, first, to discuss the molecular and cellular underpinnings of VLCFA-induced oxidative stress, and how it interacts with energy metabolism and/or inflammation to generate a complex syndrome wherein multiple factors are contributing. Particular attention will be paid to the dysregulation of redox homeostasis by the interplay between peroxisomes and mitochondria. Second, we will extend this analysis to the aforementioned neurodegenerative diseases with the aim of defining differences as well as the existence of a core pathogenic mechanism that would justify the exchange of therapeutic opportunities among these pathologies. This article is part of a Special Issue entitled: Metabolic functions and biogenesis of peroxisomes in health and disease. The work of the authors of this review was supported by grants from the European Commission (FP7-241622), the European Leukodystrophy Association (ELA2009-041D6; ELA2008-040C4), the Oliver's Army, the Spanish Institute for Health Carlos III (FIS PI080991), and the Autonomous Government of Catalonia (2009SGR85) to A.P. Centro de Investigación en Red sobre Enfermedades Raras (CIBERER) is an initiative of the Instituto de Salud Carlos III. The study was developed under the COST action BM0604 (to A.P.). 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 [BFU2009-11879/BFI], the Spanish Ministry of Health [PI081843, PI0111532], the Autonomous Government of Catalonia [2009SGR735], ‘La Caixa’ Foundation, and COST B35 Action of the European Union to M.P.O. and R.P.