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

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

doi:https://doi.org/10.1093/brain/awt143

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Fecha de publicación

2013

Autor/a

Morató, Laia

Galino, Jorge

Ruiz, Montserrat

Calingasan, Noel Ylagan

Starkov, Anatoly A.

Dumont, Magali

Naudí i Farré, Alba

Martínez, Juan José

Aubourg, Patrick

Portero Otín, Manuel

Pamplona Gras, Reinald

Galea, Elena

Flint Beal, M.

Ferrer, Isidre

Fourcade, Stéphane

Pujol, Aurora

Cita recomendada

Morató, Laia; Galino, Jorge; Ruiz, Montserrat; Calingasan, Noel Ylagan; Starkov, Anatoly A.; Dumont, Magali; ... Pujol, Aurora. (2013) . Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy. Brain: a journal of neurology, 2013, vol. 136, núm. 8, p. 2432-2443. https://doi.org/10.1093/brain/awt143.

Resumen

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.

URI

http://hdl.handle.net/10459.1/58503

DOI

https://doi.org/10.1093/brain/awt143

Es parte de

Brain: a journal of neurology, 2013, vol. 136, núm. 8, p. 2432-2443