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Open AccessArticle

Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network

1
Department of Pathology and Laboratory Medicine, University of Western Ontario, London, ON N6A 5C1, Canada
2
Clinical Neurological Sciences, University of Western Ontario, London, ON N6A 5C1, Canada
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(16), 5597; https://doi.org/10.3390/ijms21165597
Received: 25 June 2020 / Revised: 15 July 2020 / Accepted: 31 July 2020 / Published: 5 August 2020
(This article belongs to the Special Issue Protein Misfolding in Health and Diseases)
The Rho guanine nucleotide exchange factor (RGNEF) protein encoded by the ARHGEF28 gene has been implicated in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Biochemical and pathological studies have shown that RGNEF is a component of the hallmark neuronal cytoplasmic inclusions in ALS-affected neurons. Additionally, a heterozygous mutation in ARHGEF28 has been identified in a number of familial ALS (fALS) cases that may give rise to one of two truncated variants of the protein. Little is known about the normal biological function of RGNEF or how it contributes to ALS pathogenesis. To further explore RGNEF biology we have established and characterized a yeast model and characterized RGNEF expression in several mammalian cell lines. We demonstrate that RGNEF is toxic when overexpressed and forms inclusions. We also found that the fALS-associated mutation in ARGHEF28 gives rise to an inclusion-forming and toxic protein. Additionally, through unbiased screening using the split-ubiquitin system, we have identified RGNEF-interacting proteins, including two ALS-associated proteins. Functional characterization of other RGNEF interactors identified in our screen suggest that RGNEF functions as a microtubule regulator. Our findings indicate that RGNEF misfolding and toxicity may cause impairment of the microtubule network and contribute to ALS pathogenesis. View Full-Text
Keywords: RGNEF; ALS; yeast model; protein misfolding; microtubules; neurodegeneration RGNEF; ALS; yeast model; protein misfolding; microtubules; neurodegeneration
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MDPI and ACS Style

Di Gregorio, S.E.; Volkening, K.; Strong, M.J.; Duennwald, M.L. Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network. Int. J. Mol. Sci. 2020, 21, 5597. https://doi.org/10.3390/ijms21165597

AMA Style

Di Gregorio SE, Volkening K, Strong MJ, Duennwald ML. Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network. International Journal of Molecular Sciences. 2020; 21(16):5597. https://doi.org/10.3390/ijms21165597

Chicago/Turabian Style

Di Gregorio, Sonja E.; Volkening, Kathryn; Strong, Michael J.; Duennwald, Martin L. 2020. "Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network" Int. J. Mol. Sci. 21, no. 16: 5597. https://doi.org/10.3390/ijms21165597

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