Mitochondrial dysfunction and oxidative damage cooperatively fuel axonal degeneration in X-linked adrenoleukodystrophy.
X-linked adrenoleukodystrophy (X-ALD) is the most frequent inherited monogenic demyelinating disease (minimal incidence 1:17,000). It is often lethal and currently lacks a satisfactory therapy. The disease is caused by loss of function of the ABCD1 gene, a peroxisomal ATP-binding cassette transporter, resulting in the accumulation of VLCFA (very long-chain fatty acids) in organs and plasma. Understanding of the aetiopathogenesis is a prerequisite for the development of novel therapeutic strategies. Functional genomics analysis of an ABCD1 null mouse, a mouse model for adrenomyeloneuropathy, has revealed presymptomatic alterations in several metabolic pathways converging on redox and bioenergetic homeostasis, with failure of mitochondrial OXPHOS disruption and mitochondrial depletion. These defects could be major contributors to the neurodegenerative cascade, as has been reported in several neurodegenerative disorders. Drugs targeting the redox imbalance/mitochondria dysfunction interplay have shown efficacy at halting axonal degeneration and associated disability in the mouse, and thus offer therapeutic hope.
Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain; Institute 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.
Stéphane
S
Fourcade
Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain; Institute 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.
Jone
J
López-Erauskin
Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain; Institute 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.
Montserrat
M
Ruiz
Institute 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.
Isidre
I
Ferrer
Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain; Institute 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), 08010 Barcelona, Spain. Electronic address: apujol@idibell.cat.
Aurora
A
Pujol
D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency*; D000326:Adrenoleukodystrophy / Q000503:physiopathology*; D000818:Animals; D001369:Axons / Q000473:pathology*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000473:pathology; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C552836:Abcd1 protein, mouse; D005227:Fatty Acids; D046988:Proteasome Endopeptidase Complex
Cyclophilin D; Mitochondria dysfunction; Oxidative damage; Proteasome; Very long-chain fatty acids; X-linked adrenoleukodystrophy