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- Title
Inhibition of Cytohesins Protects against Genetic Models of Motor Neuron Disease.
- Authors
Jinbin Zhai; Lei Zhang; Mojsilovic-Petrovic, Jelena; Xiaoying Jian; Thomas, Jeffrey; Homma, Kengo; Schmitz, Anton; Famulok, Michael; Ichijo, Hidenori; Argon, Yair; Randazzo, Paul A.; Kalb, Robert G.
- 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 inGEFactivity orARFactivation.ERstress evoked by mutantSOD1expression 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.
- Subjects
CYTOHESINS; MOTOR neuron diseases; AMYOTROPHIC lateral sclerosis; PATHOLOGICAL physiology; ENDOPLASMIC reticulum; AUTOPHAGY; GENETICS
- Publication
Journal of Neuroscience, 2015, Vol 35, Issue 24, p9088
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5032-13.2015