Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons
- New York University, United States
- Boston Children's Hospital, United States
- Columbia University Medical Center, United States
- Boston Childrens Hospital, United States
Abstract
In amyotrophic lateral sclerosis (ALS) spinal motor neurons (SpMN) progressively degenerate while a subset of cranial motor neurons (CrMN) are spared until late stages of the disease. Using a rapid and efficient protocol to differentiate mouse embryonic stem cells (ESC) to SpMNs and CrMNs, we now report that ESC-derived CrMNs accumulate less human (h)SOD1 and insoluble p62 than SpMNs over time. ESC-derived CrMNs have higher proteasome activity to degrade misfolded proteins and are intrinsically more resistant to chemically-induced proteostatic stress than SpMNs. Chemical and genetic activation of the proteasome rescues SpMN sensitivity to proteostatic stress. In agreement, the hSOD1 G93A mouse model reveals that ALS-resistant CrMNs accumulate less insoluble hSOD1 and p62-containing inclusions than SpMNs. Primary-derived ALS-resistant CrMNs are also more resistant than SpMNs to proteostatic stress. Thus, an ESC-based platform has identified a superior capacity to maintain a healthy proteome as a possible mechanism to resist ALS-induced neurodegeneration.
Data availability
Sequencing data have been deposited in GEO under accession code GSE130938.
Article and author information
Author details
Dylan E Iannitelli
Esteban Orlando Mazzoni
Funding
PROJECT ALS (A13-0416)
- Esteban Orlando Mazzoni
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD079682)
- Esteban Orlando Mazzoni
NYDH (DOH01-C32243GG-3450000)
- Esteban Orlando Mazzoni
MODBDF (#5-FY14-99)
- Esteban Orlando Mazzoni
National Institute of Neurological Disorders and Stroke (F31 NS 095571)
- John W Smerdon
National Institute of Neurological Disorders and Stroke (F31 103447)
- Dylan E Iannitelli
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Protocols were approved by Columbia University and Harvard University
Copyright
© 2019, An et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons
eLife 8:e44423.
https://doi.org/10.7554/eLife.44423
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