Stem Cell-Derived Cranial and Spinal Motor Neurons Reveal Proteostatic Differences between ALS Resistant and Sensitive Motor Neurons

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 superoxide dismutase 1 (hSOD1) and insoluble p62 than SpMNs over time. ESC-derived CrMNs rely more on the ubiquitin proteasome system to degrade misfolded proteins and are intrinsically more resistant to chemically-induced proteostatic stress than SpMNs. Moreover, chemical activation of the proteasome rescues the SpMN sensitivity to proteostatic stress. Confirming the in vitro observations, ALS-resistant CrMNs accumulate less insoluble hSOD1 and p62-containing inclusions than SpMNs in the hSOD1 G93A mouse model. Primary ALS-resistant CrMNs are also more resistant than SpMNs to proteostatic stress. Together, these results establish an ESC-based platform to study differential ALS vulnerability and identify the greater capacity to maintain a healthier proteome, a possible mechanism to resist ALS-induced neurodegeneration.