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Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin

Loss of cellular homeostasis has been implicated in the etiology of several neurodegenerative diseases (NDs). However, the molecular mechanisms that underlie this loss remain poorly understood on a systems level in each case. Here, using a novel computational approach to integrate dimensional RNA-se...

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Autores principales: Megret, Lucile, Gris, Barbara, Sasidharan Nair, Satish, Cevost, Jasmin, Wertz, Mary, Aaronson, Jeff, Rosinski, Jim, Vogt, Thomas F, Wilkinson, Hilary, Heiman, Myriam, Neri, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901871/
https://www.ncbi.nlm.nih.gov/pubmed/33618800
http://dx.doi.org/10.7554/eLife.64984
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author Megret, Lucile
Gris, Barbara
Sasidharan Nair, Satish
Cevost, Jasmin
Wertz, Mary
Aaronson, Jeff
Rosinski, Jim
Vogt, Thomas F
Wilkinson, Hilary
Heiman, Myriam
Neri, Christian
author_facet Megret, Lucile
Gris, Barbara
Sasidharan Nair, Satish
Cevost, Jasmin
Wertz, Mary
Aaronson, Jeff
Rosinski, Jim
Vogt, Thomas F
Wilkinson, Hilary
Heiman, Myriam
Neri, Christian
author_sort Megret, Lucile
collection PubMed
description Loss of cellular homeostasis has been implicated in the etiology of several neurodegenerative diseases (NDs). However, the molecular mechanisms that underlie this loss remain poorly understood on a systems level in each case. Here, using a novel computational approach to integrate dimensional RNA-seq and in vivo neuron survival data, we map the temporal dynamics of homeostatic and pathogenic responses in four striatal cell types of Huntington’s disease (HD) model mice. This map shows that most pathogenic responses are mitigated and most homeostatic responses are decreased over time, suggesting that neuronal death in HD is primarily driven by the loss of homeostatic responses. Moreover, different cell types may lose similar homeostatic processes, for example, endosome biogenesis and mitochondrial quality control in Drd1-expressing neurons and astrocytes. HD relevance is validated by human stem cell, genome-wide association study, and post-mortem brain data. These findings provide a new paradigm and framework for therapeutic discovery in HD and other NDs.
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spelling pubmed-79018712021-02-24 Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin Megret, Lucile Gris, Barbara Sasidharan Nair, Satish Cevost, Jasmin Wertz, Mary Aaronson, Jeff Rosinski, Jim Vogt, Thomas F Wilkinson, Hilary Heiman, Myriam Neri, Christian eLife Computational and Systems Biology Loss of cellular homeostasis has been implicated in the etiology of several neurodegenerative diseases (NDs). However, the molecular mechanisms that underlie this loss remain poorly understood on a systems level in each case. Here, using a novel computational approach to integrate dimensional RNA-seq and in vivo neuron survival data, we map the temporal dynamics of homeostatic and pathogenic responses in four striatal cell types of Huntington’s disease (HD) model mice. This map shows that most pathogenic responses are mitigated and most homeostatic responses are decreased over time, suggesting that neuronal death in HD is primarily driven by the loss of homeostatic responses. Moreover, different cell types may lose similar homeostatic processes, for example, endosome biogenesis and mitochondrial quality control in Drd1-expressing neurons and astrocytes. HD relevance is validated by human stem cell, genome-wide association study, and post-mortem brain data. These findings provide a new paradigm and framework for therapeutic discovery in HD and other NDs. eLife Sciences Publications, Ltd 2021-02-23 /pmc/articles/PMC7901871/ /pubmed/33618800 http://dx.doi.org/10.7554/eLife.64984 Text en © 2021, Megret et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Computational and Systems Biology
Megret, Lucile
Gris, Barbara
Sasidharan Nair, Satish
Cevost, Jasmin
Wertz, Mary
Aaronson, Jeff
Rosinski, Jim
Vogt, Thomas F
Wilkinson, Hilary
Heiman, Myriam
Neri, Christian
Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin
title Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin
title_full Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin
title_fullStr Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin
title_full_unstemmed Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin
title_short Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin
title_sort shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin
topic Computational and Systems Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901871/
https://www.ncbi.nlm.nih.gov/pubmed/33618800
http://dx.doi.org/10.7554/eLife.64984
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