title: Inhibition of Cytohesins Protects against Genetic Models of Motor Neuron Disease.
abstract: Mutant genes that underlie Mendelian forms of amyotrophic lateral sclerosis (ALS) and biochemical investigations of genetic disease models point to potential driver pathophysiological events involving endoplasmic reticulum (ER) stress and autophagy. Several steps in these cell biological processes are known to be controlled physiologically by small ADP-ribosylation factor (ARF) signaling. Here, we investigated the role of ARF guanine nucleotide exchange factors (GEFs), cytohesins, in models of ALS. Genetic or pharmacological inhibition of cytohesins protects motor neurons in vitro from proteotoxic insults and rescues locomotor defects in a Caenorhabditis elegans model of disease. Cytohesins form a complex with mutant superoxide dismutase 1 (SOD1), a known cause of familial ALS, but this is not associated with a change in GEF activity or ARF activation. ER stress evoked by mutant SOD1 expression is alleviated by antagonism of cytohesin activity. In the setting of mutant SOD1 toxicity, inhibition of cytohesin activity enhances autophagic flux and reduces the burden of misfolded SOD1. These observations suggest that targeting cytohesins may have potential benefits for the treatment of ALS.
authors.affiliation: Division of Pediatric Neurology and.
authors.forename: Jinbin
authors.initials: J
authors.lastname: Zhai
authors.affiliation: Division of Pediatric Neurology and.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Pediatric Neurology and.
authors.forename: Jelena
authors.initials: J
authors.lastname: Mojsilovic-Petrovic
authors.affiliation: Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Jian
authors.affiliation: Division of Cell Pathology, Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Jeffrey
authors.identifier: http://orcid.org/0000-0003-4814-3281
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Laboratory of Cell Signaling, University of Tokyo, Tokyo, Japan 113-0033.
authors.forename: Kengo
authors.initials: K
authors.lastname: Homma
authors.affiliation: Life and Medical Sciences Institute, University of Bonn, 53121 Bonn, Germany, and.
authors.forename: Anton
authors.initials: A
authors.lastname: Schmitz
authors.affiliation: Life and Medical Sciences Institute, University of Bonn, 53121 Bonn, Germany, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Famulok
authors.affiliation: Laboratory of Cell Signaling, University of Tokyo, Tokyo, Japan 113-0033.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.affiliation: Division of Cell Pathology, Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Yair
authors.initials: Y
authors.lastname: Argon
authors.affiliation: Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Randazzo
authors.affiliation: Division of Pediatric Neurology and Department of Neurology and Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, kalb@email.chop.edu.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kalb
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D016472:Motor Neuron Disease / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; C000599612:GRP-1 protein, C elegans; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; C102474:cytohesin-2; C587809:Sod-1 protein, C elegans; D013482:Superoxide Dismutase
keywords: ALS; ER stress; autophagy; proteotoxicity; unfolded protein response