Analyzing the ER stress response in ALS patient derived motor neurons identifies druggable neuroprotective targets
Year: 2024
Type: article
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 MAP4K4i-mediated 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.
Institutions: Harvard University, Harvard Stem Cell Institute
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,295
Awards: Understanding Roles for Protein Homeostasis Machinery in Aging Brain Vasculature, G5918985142, Systematic discovery and functional analysis of the PARKIN modified proteome, Regulation of PINK1 and PARKIN-Dependent Mitophagy, G9000001739, Endolysosomal Proteome Landscapes Through the Lens of Neurodegenerative Risk Alleles
OpenAlex ID: W4391033422