title: Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy.
abstract: The activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors transduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigated the role of a chronically activated UPR in the pathogenesis of X-linked adrenoleukodystrophy (X-ALD), a neurometabolic disorder that is caused by ABCD1 malfunction; ABCD1 transports very long-chain fatty acids (VLCFA) into peroxisomes. The disease manifests as inflammatory demyelination in the brain or and/or degeneration of corticospinal tracts, thereby resulting in spastic paraplegia, with the accumulation of intracellular VLCFA instead of protein aggregates. Using X-ALD mouse model (Abcd1-and Abcd1-/Abcd2-/-mice) and X-ALD patient's fibroblasts and brain samples, we discovered an early engagement of the UPR. The response was characterized by the activation of the PERK and ATF6 pathways, but not the IRE1 pathway, showing a difference from the models of AD, PD or ALS. Inhibition of PERK leads to the disruption of homeostasis and increased apoptosis during ER stress induced in X-ALD fibroblasts. Redox imbalance appears to be the mechanism that initiates ER stress in X-ALD. Most importantly, we demonstrated that the bile acid tauroursodeoxycholate (TUDCA) abolishes UPR activation, which results in improvement of axonal degeneration and its associated locomotor impairment in Abcd1-/Abcd2-/-mice. Altogether, our preclinical data provide evidence for establishing the UPR as a key drug target in the pathogenesis cascade. Our study also highlights the potential role of TUDCA as a treatment for X-ALD and other axonopathies in which similar molecular mediators are implicated.
authors.affiliation: Neurometabolic Diseases Laboratory, Institut de Neuropatologia de Bellvitge, IDIBELL, Gran Via, 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.|CIBERER U759, Center for Biomedical Research on Rare Diseases, Barcelona, Spain.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Launay
authors.affiliation: Neurometabolic Diseases Laboratory, Institut de Neuropatologia de Bellvitge, IDIBELL, Gran Via, 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.|CIBERER U759, Center for Biomedical Research on Rare Diseases, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Ruiz
authors.affiliation: Neurometabolic Diseases Laboratory, Institut de Neuropatologia de Bellvitge, IDIBELL, Gran Via, 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.|CIBERER U759, Center for Biomedical Research on Rare Diseases, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Grau
authors.affiliation: Neurometabolic Diseases Laboratory, Institut de Neuropatologia de Bellvitge, IDIBELL, Gran Via, 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.|CIBERER U759, Center for Biomedical Research on Rare Diseases, Barcelona, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Ortega
authors.affiliation: Neurometabolic Diseases Laboratory, Institut de Neuropatologia de Bellvitge, IDIBELL, Gran Via, 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.|CIBERER U759, Center for Biomedical Research on Rare Diseases, Barcelona, Spain.|Global data, London, UK.
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Ilieva
authors.affiliation: Neurometabolic Diseases Laboratory, Institut de Neuropatologia de Bellvitge, IDIBELL, Gran Via, 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.|CIBERER U759, Center for Biomedical Research on Rare Diseases, Barcelona, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Martínez
authors.affiliation: Institute of Neurosciences, Universitat Autònoma de Barcelona, Barcelona, Spain.|Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Galea
authors.affiliation: Institute of Neuropathology, Pathologic Anatomy Service, IDIBELL, Barcelona, Spain.|Department of Pathology and Experimental Therapeutics, University of Barcelona, 08908, L'Hospitalet de Llobregat, Barcelona, Spain.|CIBERNED, Center for Biomedical Research on Neurodegenerative Diseases, Barcelona, Spain.
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: Laboratory of Cellular Biology, Centro de Investigación Príncipe Felipe, 46012, Valencia, Spain.|CIBERER U721, Center for Biomedical Research on Rare Diseases, Valencia, Spain.
authors.forename: Erwin
authors.initials: E
authors.lastname: Knecht
authors.affiliation: Neurometabolic Diseases Laboratory, Institut de Neuropatologia de Bellvitge, IDIBELL, Gran Via, 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain. apujol@idibell.cat.|CIBERER U759, Center for Biomedical Research on Rare Diseases, Barcelona, Spain. apujol@idibell.cat.|Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain. apujol@idibell.cat.
authors.forename: Aurora
authors.identifier: 0000-0002-9606-0600
authors.initials: A
authors.lastname: Pujol
authors.affiliation: Neurometabolic Diseases Laboratory, Institut de Neuropatologia de Bellvitge, IDIBELL, Gran Via, 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain. sfourcade@idibell.cat.|CIBERER U759, Center for Biomedical Research on Rare Diseases, Barcelona, Spain. sfourcade@idibell.cat.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fourcade
mesh_terms: D000326:Adrenoleukodystrophy / Q000503:physiopathology*; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000503:physiopathology*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine
keywords: Adrenoleukodystrophy; ER stress; Neurodegeneration; Oxidative stress; Peroxisome; TUDCA; UPR