title: Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: A paradigm for axonal degeneration.
abstract: Peroxisomal and mitochondrial malfunction, which are highly intertwined through redox regulation, in combination with defective proteostasis, are hallmarks of the most prevalent multifactorial neurodegenerative diseases-including Alzheimer's (AD) and Parkinson's disease (PD)-and of the aging process, and are also found in inherited conditions. Here we review the interplay between oxidative stress and axonal degeneration, taking as groundwork recent findings on pathomechanisms of the peroxisomal neurometabolic disease adrenoleukodystrophy (X-ALD). We explore the impact of chronic redox imbalance caused by the excess of very long-chain fatty acids (VLCFA) on mitochondrial respiration and biogenesis, and discuss how this impairs protein quality control mechanisms essential for neural cell survival, such as the proteasome and autophagy systems. As consequence, prime molecular targets in the pathogenetic cascade emerge, such as the SIRT1/PGC-1α axis of mitochondrial biogenesis, and the inhibitor of autophagy mTOR. Thus, we propose that mitochondria-targeted antioxidants; mitochondrial biogenesis boosters such as the antidiabetic pioglitazone and the SIRT1 ligand resveratrol; and the autophagy activator temsirolimus, a derivative of the mTOR inhibitor rapamycin, hold promise as disease-modifying therapies for X-ALD.
authors.affiliation: Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, 08908 Barcelona, Spain; Institut of Neuropathology, Pathologic Anatomy Service, Bellvitge Biomedical Research Institute, IDIBELL-Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, 08908 Barcelona, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), U759, ISCIII, Spain. Electronic address: sfourcade@idibell.cat.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fourcade
authors.affiliation: Institut of Neuropathology, Pathologic Anatomy Service, Bellvitge Biomedical Research Institute, IDIBELL-Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, 08908 Barcelona, Spain; Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Spain.
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, 08908 Barcelona, Spain; Institut of Neuropathology, Pathologic Anatomy Service, Bellvitge Biomedical Research Institute, IDIBELL-Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, 08908 Barcelona, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), U759, ISCIII, Spain; Catalan Institution of Research and Advanced Studies (ICREA), Barcelona 08010, Catalonia, Spain. Electronic address: apujol@idibell.cat.
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
mesh_terms: D000326:Adrenoleukodystrophy / Q000150:complications / Q000503:physiopathology*; D000818:Animals; D001369:Axons; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000503:physiopathology*; D018384:Oxidative Stress; D020675:Peroxisomes / Q000378:metabolism*; D057165:Proteostasis Deficiencies / Q000209:etiology / Q000503:physiopathology*
keywords: Autophagy; Mitochondrial dysfunction; Oxidative damage; Peroxisome; Proteasome; Very long-chain fatty acids; X-linked adrenoleukodystrophy