Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy

Laia Morató, Jorge Galino, Montserrat Ruiz, Noel Ylagan Calingasan, Anatoly A. Starkov, Magali Dumont, Alba Naudí, Juan José Martínez, Patrick Aubourg, Manuel Portero-Otín, Reinald Pamplona, Elena Galea, M. Flint Beal, Isidre Ferrer, Stéphane Fourcade, Aurora Pujol

Research output: Contribution to journalArticleResearchpeer-review

47 Citations (Scopus)

Abstract

X-linked adrenoleukodystrophy is a neurometabolic disorder caused by inactivation of the peroxisomal ABCD1 transporter of very long-chain fatty acids. In mice, ABCD1 loss causes late onset axonal degeneration in the spinal cord in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. Increasing evidence indicates that oxidative stress and bioenergetic failure play major roles in the pathogenesis of X-linked adrenoleukodystrophy. In this study, we aimed to evaluate whether mitochondrial biogenesis is affected in X-linked adrenoleukodystrophy. We demonstrated that Abcd1 null mice show reduced mitochondrial DNA concomitant with downregulation of mitochondrial biogenesis pathway driven by PGC-1α/PPARγ and reduced expression of mitochondrial proteins cytochrome c, NDUFB8 and VDAC. Moreover, we show that the oral administration of pioglitazone, an agonist of PPARγ, restored mitochondrial content and expression of master regulators of biogenesis, neutralized oxidative damage to proteins and DNA, and reversed bioenergetic failure in terms of ATP levels, NAD+/NADH ratios, pyruvate kinase and glutathione reductase activities. Most importantly, the treatment halted locomotor disability and axonal damage in X-linked adrenoleukodystrophy mice. These results lend support to the use of pioglitazone in clinical trials with patients with adrenomyeloneuropathy and reveal novel molecular mechanisms of action of pioglitazone in neurodegeneration. Future studies should address the effects of this anti-diabetic drug on other axonopathies in which oxidative stress and mitochondrial dysfunction are contributing factors. © The Author (2013).
Original languageEnglish
Pages (from-to)2432-2443
JournalBrain
Volume136
DOIs
Publication statusPublished - 1 Jan 2013

Keywords

  • Axonal degeneration
  • Mitochondrial biogenesis
  • Oxidative stress
  • Pioglitazone
  • X-linked adrenoleukodystrophy

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