title: 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.affiliation: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L' Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Launay
authors.forename: Carmen
authors.initials: C
authors.lastname: Aguado
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fourcade
authors.forename: Montserrat
authors.initials: M
authors.lastname: Ruiz
authors.forename: Laia
authors.initials: L
authors.lastname: Grau
authors.forename: Jordi
authors.initials: J
authors.lastname: Riera
authors.forename: Cristina
authors.initials: C
authors.lastname: Guilera
authors.forename: Marisa
authors.initials: M
authors.lastname: Giròs
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Erwin
authors.initials: E
authors.lastname: Knecht
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
mesh_terms: D000326:Adrenoleukodystrophy / Q000473:pathology* / Q000503:physiopathology*; D000328:Adult; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D058570:TOR Serine-Threonine Kinases