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

作者：Launay Nathalie; Aguado Carmen; Fourcade Stephane; Ruiz Montserrat; Grau Laia; Riera Jordi; Guilera Cristina; Giros Marisa; Ferrer Isidre; Knecht Erwin; Pujol Aurora^*

来源：Acta Neuropathologica, 2015, 129(3): 399-415.

DOI：10.1007/s00401-014-1378-8

• X-ALD
• Autophagy
• mTOR
• Temsirolimus
• VLCFA

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.

• 出版日期2015-3