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Inhibition of Cytohesins Protects against Genetic Models of Motor Neuron Disease.

The Journal of neuroscience : the official journal of the Society for Neuroscience (2015-06-19)
Jinbin Zhai, Lei Zhang, Jelena Mojsilovic-Petrovic, Xiaoying Jian, Jeffrey Thomas, Kengo Homma, Anton Schmitz, Michael Famulok, Hidenori Ichijo, Yair Argon, Paul A Randazzo, Robert G Kalb
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.

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