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

Elena Galea, Nathalie Launay, Manuel Portero-Otin, Montserrat Ruiz, Reinald Pamplona, Patrick Aubourg, Isidre Ferrer, Aurora Pujol

Research output: Contribution to journalReview articleResearchpeer-review

67 Citations (Scopus)

Abstract

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. © 2012 Elsevier B.V..
Original languageEnglish
Pages (from-to)1475-1488
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1822
Issue number9
DOIs
Publication statusPublished - 1 Sep 2012

Keywords

  • Adrenoleukodystrophy
  • Fatty acid
  • Metabolic failure
  • Mitochondria
  • Neurodegenerative disease
  • Oxidative stress

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