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Analyzing the ER stress response in ALS patient derived motor neurons identifies druggable neuroprotective targets.

Authors :
Watts, Michelle E.
Giadone, Richard M.
Ordureau, Alban
Holton, Kristina M.
Harper, J. Wade
Rubin, Lee L.
Source :
Frontiers in Cellular Neuroscience; 2024, p1-20, 20p
Publication Year :
2024

Abstract

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron (MN) disease with severely limited treatment options. Identification of effective treatments has been limited in part by the lack of predictive animal models for complex human disorders. Here, we utilized pharmacologic ER stressors to exacerbate underlying sensitivities conferred by ALS patient genetics in induced pluripotent stem cell (iPSC)-derived motor neurons (MNs). In doing so, we found that thapsigargin and tunicamycin exposure recapitulated ALS-associated degeneration, and that we could rescue this degeneration via MAP4K4 inhibition (MAP4K4i). We subsequently identified mechanisms underlying MAP4K4imediated protection by performing phosphoproteomics on iPSC-derived MNs treated with ER stressors MAP4K4i. Through these analyses, we found JNK, PKC, and BRAF to be differentially modulated in MAP4K4i-protected MNs, and that inhibitors to these proteins could also rescue MN toxicity. Collectively, this study highlights the value of utilizing ER stressors in ALS patient MNs to identify novel druggable targets. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
16625102
Database :
Complementary Index
Journal :
Frontiers in Cellular Neuroscience
Publication Type :
Academic Journal
Accession number :
175403469
Full Text :
https://doi.org/10.3389/fncel.2023.1327361