Autophagy induction halts axonal degeneration in a mouse model of X-adrenoleukodystrophy.

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the accumulation of very long chain fatty acids (VLCFAs) due to a loss of function of the peroxisomal transporter ABCD1. Here, using in vivo and in vitro models, we demonstrate that autophagic flux was impaired due to elevated mammalian target of rapamycin (mTOR) signaling, which contributed to X-ALD pathogenesis. We also show that excess VLCFAs downregulated autophagy in human fibroblasts. Furthermore, mTOR inhibition by a rapamycin derivative (temsirolimus) restored autophagic flux and inhibited the axonal degenerative process as well as the associated locomotor impairment in the Abcd1 (-) /Abcd2 (-/-) mouse model. This process was mediated through the restoration of proteasome function and redox as well as metabolic homeostasis. These findings provide the first evidence that links impaired autophagy to X-ALD, which may yield a therapy based on autophagy activators for adrenomyeloneuropathy patients.

• Authors: Nathalie Launay, Carmen Aguado, Stéphane Fourcade, Montserrat Ruiz, Laia Grau, Jordi Riera, Cristina Guilera, Marisa Giròs, Isidre Ferrer, Erwin Knecht, Aurora Pujol
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 129 Issue 3 Pg. 399-415 (Mar 2015) ISSN: 1432-0533 [Electronic] Germany
• PMID: 25549970 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• TOR Serine-Threonine Kinases

Topics

• Adrenoleukodystrophy (pathology, physiopathology)
• Adult
• Animals
• Autophagy (physiology)
• Blotting, Western
• Cells, Cultured
• Disease Models, Animal
• Female
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Knockout
• Microscopy, Electron, Transmission
• Middle Aged
• Nerve Degeneration (pathology, physiopathology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (physiology)
• TOR Serine-Threonine Kinases (metabolism)