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Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology

Matrin-3 (MATR3) is a DNA- and RNA-binding protein implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and distal myopathy. Here, we report the development of a yeast model of MATR3 proteotoxicity and aggregation. MATR3 is toxic and forms dynamic shell-like nuclear cond...

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Autores principales: Sprunger, Macy L., Lee, Ken, Sohn, Brian S., Jackrel, Meredith E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8889142/
https://www.ncbi.nlm.nih.gov/pubmed/35252808
http://dx.doi.org/10.1016/j.isci.2022.103900
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author Sprunger, Macy L.
Lee, Ken
Sohn, Brian S.
Jackrel, Meredith E.
author_facet Sprunger, Macy L.
Lee, Ken
Sohn, Brian S.
Jackrel, Meredith E.
author_sort Sprunger, Macy L.
collection PubMed
description Matrin-3 (MATR3) is a DNA- and RNA-binding protein implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and distal myopathy. Here, we report the development of a yeast model of MATR3 proteotoxicity and aggregation. MATR3 is toxic and forms dynamic shell-like nuclear condensates in yeast. Disease-associated mutations in MATR3 impair condensate dynamics and disrupt condensate morphology. MATR3 toxicity is largely driven by its RNA-recognitions motifs (RRMs). Further, deletion of one or both RRMs drives coalescence of these condensates. Aberrant phase separation of several different RBPs underpins ALS/FTD, and we have engineered Hsp104 variants to reverse this misfolding. Here, we demonstrate that these same variants also counter MATR3 toxicity. We suggest that these Hsp104 variants which rescue MATR3, TDP-43, and FUS toxicity might be employed against a range of ALS/FTD-associated proteins. We anticipate that our yeast model could be a useful platform to screen for modulators of MATR3 misfolding.
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spelling pubmed-88891422022-03-03 Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology Sprunger, Macy L. Lee, Ken Sohn, Brian S. Jackrel, Meredith E. iScience Article Matrin-3 (MATR3) is a DNA- and RNA-binding protein implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and distal myopathy. Here, we report the development of a yeast model of MATR3 proteotoxicity and aggregation. MATR3 is toxic and forms dynamic shell-like nuclear condensates in yeast. Disease-associated mutations in MATR3 impair condensate dynamics and disrupt condensate morphology. MATR3 toxicity is largely driven by its RNA-recognitions motifs (RRMs). Further, deletion of one or both RRMs drives coalescence of these condensates. Aberrant phase separation of several different RBPs underpins ALS/FTD, and we have engineered Hsp104 variants to reverse this misfolding. Here, we demonstrate that these same variants also counter MATR3 toxicity. We suggest that these Hsp104 variants which rescue MATR3, TDP-43, and FUS toxicity might be employed against a range of ALS/FTD-associated proteins. We anticipate that our yeast model could be a useful platform to screen for modulators of MATR3 misfolding. Elsevier 2022-02-11 /pmc/articles/PMC8889142/ /pubmed/35252808 http://dx.doi.org/10.1016/j.isci.2022.103900 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Sprunger, Macy L.
Lee, Ken
Sohn, Brian S.
Jackrel, Meredith E.
Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology
title Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology
title_full Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology
title_fullStr Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology
title_full_unstemmed Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology
title_short Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology
title_sort molecular determinants and modifiers of matrin-3 toxicity, condensate dynamics, and droplet morphology
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8889142/
https://www.ncbi.nlm.nih.gov/pubmed/35252808
http://dx.doi.org/10.1016/j.isci.2022.103900
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