Inhibition of cytohesins protects against genetic models of motor neuron disease

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*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)9088-9105
Number of pages18
JournalJournal of Neuroscience
Volume35
Issue number24
DOIs
StatePublished - Jun 17 2015

Fingerprint

Motor Neuron Disease
Genetic Models
Amyotrophic Lateral Sclerosis
ADP-Ribosylation Factors
Biological Phenomena
Guanine Nucleotide Exchange Factors
Inborn Genetic Diseases
Endoplasmic Reticulum Stress
Autophagy
Caenorhabditis elegans
Motor Neurons
Molecular Biology
Pharmacology
Genes
Superoxide Dismutase-1

Keywords

  • ALS
  • Autophagy
  • ER stress
  • Proteotoxicity
  • Unfolded protein response

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Zhai, Jinbin ; Zhang, Lei ; Mojsilovic-Petrovic, Jelena ; Jian, Xiaoying ; Thomas, Jeffrey ; Homma, Kengo ; Schmitz, Anton ; Famulok, Michael ; Ichijo, Hidenori ; Argon, Yair ; Randazzo, Paul A. ; Kalb, Robert G. / Inhibition of cytohesins protects against genetic models of motor neuron disease. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 24. pp. 9088-9105.
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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.",
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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 2015, 'Inhibition of cytohesins protects against genetic models of motor neuron disease', Journal of Neuroscience, vol. 35, no. 24, pp. 9088-9105. https://doi.org/10.1523/JNEUROSCI.5032-13.2015

Inhibition of cytohesins protects against genetic models of motor neuron disease. / Zhai, Jinbin; Zhang, Lei; Mojsilovic-Petrovic, Jelena; Jian, Xiaoying; Thomas, Jeffrey; Homma, Kengo; Schmitz, Anton; Famulok, Michael; Ichijo, Hidenori; Argon, Yair; Randazzo, Paul A.; Kalb, Robert G.

In: Journal of Neuroscience, Vol. 35, No. 24, 17.06.2015, p. 9088-9105.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of cytohesins protects against genetic models of motor neuron disease

AU - Zhai, Jinbin

AU - Zhang, Lei

AU - Mojsilovic-Petrovic, Jelena

AU - Jian, Xiaoying

AU - Thomas, Jeffrey

AU - Homma, Kengo

AU - Schmitz, Anton

AU - Famulok, Michael

AU - Ichijo, Hidenori

AU - Argon, Yair

AU - Randazzo, Paul A.

AU - Kalb, Robert G.

PY - 2015/6/17

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N2 - 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.

AB - 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.

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KW - Proteotoxicity

KW - Unfolded protein response

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