title: Guanabenz, which enhances the unfolded protein response, ameliorates mutant SOD1-induced amyotrophic lateral sclerosis.
abstract: Approximately 20% of familial amyotrophic lateral sclerosis (FALS) cases are caused by mutant superoxide dismutase type 1 (mtSOD1). Although the mechanisms of mtSOD1-induced toxicity remain poorly understood, evidence suggests that accumulation of misfolded SOD1 is fundamental to its toxicity and the death of motor neurons. Misfolded mtSOD1 can accumulate inside the endoplasmic reticulum (ER), leading to ER stress, with activation of the unfolded protein response (UPR). We have previously carried out genetic studies focused on PERK (which is an eIF2α kinase that is rapidly activated in response to ER stress and leads to a repression in translation) and GADD34 (which participates in the dephosphorylation of eIF2α). We reported that mtSOD1 transgenic mice that are haploinsufficient for PERK have a significantly accelerated ALS disease, while mtSOD1 mice that are mutated for GADD34 have a remarkably ameliorated disease. Guanabenz, a centrally acting oral drug approved for the treatment of hypertension, enhances the PERK pathway by selectively inhibiting GADD34-mediated dephosphorylation of eIF2α. We have now treated G93A mtSOD1 transgenic mice with guanabenz and found a significant amelioration of disease with a delay in the onset and prolongation of the early phase of disease and survival. Guanabenz-treated G93A mice have less accumulation of mtSOD1 and an enhanced phosphorylation of eIF2α at endstage. This study further emphasizes the importance of the PERK pathway in the pathogenesis of FALS and as a therapeutic target in ALS, and identifies guanabenz as a candidate drug for the treatment of ALS patients.
authors.affiliation: Department of Neurology/MC2030, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Neurology/MC2030, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL 60637, USA; The University of Chicago Center for Peripheral Neuropathy, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Popko
authors.affiliation: Department of Neurology/MC2030, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Tixier
authors.affiliation: Department of Neurology/MC2030, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL 60637, USA; The University of Chicago Center for Peripheral Neuropathy, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL 60637, USA. Electronic address: rroos@neurology.bsd.uchicago.edu.
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Roos
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006143:Guanabenz / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D058767:Protein Unfolding / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000235:genetics*; D016019:Survival Analysis
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D006143:Guanabenz
keywords: Amyotrophic lateral sclerosis; Superoxide dismutase type 1; Unfolded protein response