Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin
Name
elife-64984-v1.pdf
Description
Published version
Size
3.28 MB
Format
Adobe PDF
Checksum (MD5)
2c92a9214b26f6bdb56c7d19a49708a9
Author(s)
Megret, Lucile
Gris, Barbara
Sasidharan Nair, Satish
Cevost, Jasmin
Wertz, Mary
Aaronson, Jeff
Rosinski, Jim
Vogt, Thomas F
Wilkinson, Hilary
Heiman, Myriam
Date Issued
2021
Journal
eLife
Publisher
eLife Sciences Publications, Ltd
Version
Final published version
Abstract
© Megret et al. 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.
MIT Department
Picower Institute for Learning and Memory
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.7554/elife.64984
