RRC ID 45666
Author Zhai J, Zhang L, Mojsilovic-Petrovic J, Jian X, Thomas J, Homma K, Schmitz A, Famulok M, Ichijo H, Argon Y, Randazzo PA, Kalb RG.
Title Inhibition of Cytohesins Protects against Genetic Models of Motor Neuron Disease.
Journal J Neurosci
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.
Volume 35(24)
Pages 9088-105
Published 2015-6-17
DOI 10.1523/JNEUROSCI.5032-13.2015
PII 35/24/9088
PMID 26085633
PMC PMC4469736
MeSH Amyotrophic Lateral Sclerosis / genetics Amyotrophic Lateral Sclerosis / metabolism Animals Caenorhabditis elegans Caenorhabditis elegans Proteins / antagonists & inhibitors* Caenorhabditis elegans Proteins / biosynthesis Caenorhabditis elegans Proteins / genetics* Cells, Cultured Disease Models, Animal* GTPase-Activating Proteins / antagonists & inhibitors GTPase-Activating Proteins / biosynthesis GTPase-Activating Proteins / genetics Guanine Nucleotide Exchange Factors / antagonists & inhibitors* Guanine Nucleotide Exchange Factors / biosynthesis Guanine Nucleotide Exchange Factors / genetics* HeLa Cells Humans Mice Models, Genetic Motor Neuron Disease / genetics* Rats Rats, Sprague-Dawley Superoxide Dismutase / biosynthesis Superoxide Dismutase / genetics
IF 5.674
Times Cited 6
C.elegans tm1447 tm1877