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

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...

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Autores principales: Di Gregorio, Sonja E., Volkening, Kathryn, Strong, Michael J., Duennwald, Martin L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460592/
https://www.ncbi.nlm.nih.gov/pubmed/32764283
http://dx.doi.org/10.3390/ijms21165597
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author Di Gregorio, Sonja E.
Volkening, Kathryn
Strong, Michael J.
Duennwald, Martin L.
author_facet Di Gregorio, Sonja E.
Volkening, Kathryn
Strong, Michael J.
Duennwald, Martin L.
author_sort Di Gregorio, Sonja E.
collection PubMed
description 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.
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spelling pubmed-74605922020-09-03 Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network Di Gregorio, Sonja E. Volkening, Kathryn Strong, Michael J. Duennwald, Martin L. Int J Mol Sci Article 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. MDPI 2020-08-05 /pmc/articles/PMC7460592/ /pubmed/32764283 http://dx.doi.org/10.3390/ijms21165597 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Di Gregorio, Sonja E.
Volkening, Kathryn
Strong, Michael J.
Duennwald, Martin L.
Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network
title Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network
title_full Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network
title_fullStr Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network
title_full_unstemmed Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network
title_short Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network
title_sort inclusion formation and toxicity of the als protein rgnef and its association with the microtubule network
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460592/
https://www.ncbi.nlm.nih.gov/pubmed/32764283
http://dx.doi.org/10.3390/ijms21165597
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