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Updated: May 6, 2026
ALS - Motor Neuron Disease: Mechanism and Development of New Therapies
Published on: July 29, 2007
Analyzing the ER stress response in ALS patient derived motor neurons identifies druggable neuroprotective targets
Michelle E Watts1,2, Richard M Giadone1,2, Alban Ordureau3
1Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, United States.
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.
Insights
Researchers found that exposing motor neurons (MNs) from ALS patients to ER stressors caused degeneration, which was reversed by MAP4K4 inhibition. This study identifies new therapeutic targets for amyotrophic lateral sclerosis (ALS).
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease impacting motor neurons, with limited effective treatments.
- Developing predictive models for complex human diseases like ALS remains a significant challenge in therapeutic research.
Purpose of the Study:
- To investigate the utility of pharmacologic endoplasmic reticulum (ER) stressors in modeling ALS-associated motor neuron degeneration.
- To identify novel therapeutic targets for ALS by leveraging patient-derived cells and stress-induced vulnerabilities.
Main Methods:
- Utilized induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) from ALS patients.
- Exposed MNs to ER stressors (thapsigargin, tunicamycin) to model degeneration.
- Employed MAP4K4 inhibition (MAP4K4i) as a therapeutic intervention.
- Conducted phosphoproteomics to elucidate MAP4K4i-mediated protective mechanisms.
Main Results:
- ER stress induction recapitulated ALS-associated motor neuron degeneration in patient-derived iPSC-MNs.
- MAP4K4 inhibition effectively rescued MN degeneration caused by ER stressors.
- Phosphoproteomic analysis revealed modulation of JNK, PKC, and BRAF pathways by MAP4K4i.
- Inhibitors of JNK, PKC, and BRAF also demonstrated neuroprotective effects in this model.
Conclusions:
- Pharmacologic ER stressors can serve as a valuable tool to model ALS and uncover patient-specific vulnerabilities.
- MAP4K4 inhibition represents a promising therapeutic strategy for ALS, potentially through modulation of JNK, PKC, and BRAF signaling.
- This study underscores the potential of targeting ER stress pathways for novel ALS treatments.
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