Pioglitazone halts nerve degeneration in mice with adrenoleukodystrophy

Written on Wednesday 16 July 2014

Adrenoleukodystrophy is a neurometabolic disease caused by a mutation in the gene encoding for the ABCD1 peroxisomal transporter of very long chain fatty acids. The peroxisome is the component of the cell whose role is to degrade these fatty acids.  

Mice mutated in the ABCD1 gene show a late degeneration of their nerve processes, called axons, at the level of the spinal cord, accompanied by a locomotor handicap similar to that of patients suffering from adrenomyeloneuropathy. In these animal models, oxidative stress and disruption of energy metabolism play major roles in the onset of the disease.

This study examines whether the formation of cellular energy generators, namely mitochondria, is altered in ALD mice. At the age of 12 months, a drop in the number of mitochondria implicating the PGC-1α and PPARγ factors is observed. An oral treatment with pioglitazone, an anti-diabetic drug that stimulates the PPARγ factor, allows recovery of the mitochondrial content, normalization of energetic metabolism and reduction of oxidative damage. It also allows the degeneration of axons and locomotor deficiencies to be stopped in these mice.

Thus, an early and appropriate treatment with pioglitazone seems to be an option that deserves to be tested by clinical trials. This therapy could be applied not only to adrenomyeloneuropathy but also to other diseases characterized by axonal degeneration accompanied by mitochondrial dysfunction and oxidative stress.

Disease: X-linked adrenoleukodystrophy (ALD)
Experimental models: Mice mutated in the ABCD1 gene and mice mutated in both the ABCD1 and ABCD2 genes, animal models for ALD
Study type: Therapeutic approach
Laboratory: Dr. Aurora Pujol, Laboratory of neurometabolic diseases, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
Funding: ELA

Source : L. Morató, J. Galino, M. Ruiz, N.Y. Calingasan, A.A. Starkov, M. Dumont, A. Naudí, J.J. Martínez, P. Aubourg, M. Portero-Otín, R. Pamplona, E. Galea, M.F. Beal, I. Ferrer, S. Fourcade, A. Pujol. Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy. Brain 2013, 136(Pt 8):2432-43.

Scientific information provided in collaboration with the INIST-CNRS Institute, Institute for Scientific and Technical Information