
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.21.608176
preprint
1
Article
Histone deacetylase inhibition expands cellular proteostasis repertoires to enhance neuronal stress resilience
Taylor Caitlin A
Maor-Nof Maya
Metzl-Raz Eyal http://orcid.org/0000-0002-7111-2822

Hidalgo Aaron
Yee Callista http://orcid.org/0000-0002-2928-492X

Gitler Aaron D http://orcid.org/0000-0001-8603-1526

Shen Kang
22 8 2024
2024.08.21.608176https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.21.608176
nihpp-2024.08.21.608176.pdf
Neurons are long-lived, terminally differentiated cells with limited regenerative capacity. Cellular stressors such as endoplasmic reticulum (ER) protein folding stress and membrane trafficking stress accumulate as neurons age and accompany age-dependent neurodegeneration. Current strategies to improve neuronal resilience are focused on using factors to reprogram neurons or targeting specific proteostasis pathways. We discovered a different approach. In an unbiased screen for modifiers of neuronal membrane trafficking defects, we unexpectedly identified a role for histone deacetylases (HDACs) in limiting cellular flexibility in choosing cellular pathways to respond to diverse types of stress. We show that genetic or pharmacological inactivation of HDACs results in improved neuronal health in response to ER protein folding stress and endosomal membrane trafficking stress in C. elegans and mammalian neurons. Surprisingly, HDAC inhibition enabled neurons to activate latent proteostasis pathways tailored to the nature of the individual stress, instead of generalized transcriptional upregulation. These findings shape our understanding of neuronal stress responses and suggest new therapeutic strategies to enhance neuronal resilience.
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pmc
