Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy. Academic Article uri icon

Overview

MeSH

  • ATP-Binding Cassette Transporters
  • Animals
  • Disease Models, Animal
  • Fatty Acids
  • Glutathione Reductase
  • Humans
  • Mice
  • Mice, Knockout
  • Oxidative Stress
  • Treatment Outcome

MeSH Major

  • Adrenoleukodystrophy
  • Axons
  • Hypoglycemic Agents
  • Nerve Degeneration
  • Thiazolidinediones

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.

publication date

  • August 2013

has subject area

  • ATP-Binding Cassette Transporters
  • Adrenoleukodystrophy
  • Animals
  • Axons
  • Disease Models, Animal
  • Fatty Acids
  • Glutathione Reductase
  • Humans
  • Hypoglycemic Agents
  • Mice
  • Mice, Knockout
  • Nerve Degeneration
  • Oxidative Stress
  • Thiazolidinediones
  • Treatment Outcome

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4550111

Digital Object Identifier (DOI)

  • 10.1093/brain/awt143

PubMed ID

  • 23794606

Additional Document Info

start page

  • 2432

end page

  • 2443

volume

  • 136

number

  • Pt 8