Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons

An, D.; Fujiki, R.; Iannitelli, D.; Smerdon, J.; Maity, S.; Rose, M.; Gelber, A.; Wanaselja, E.; Yagudayeva, I.; Lee, J.; Vogel, C.; Wichterle, H.; Engle, E.; Mazzoni, E.

doi:10.1101/629295

bioRxiv · 10.1101/629295

Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons

An, D.·Fujiki, R.·Iannitelli, D.·Smerdon, J.·Maity, S.·Rose, M.·Gelber, A.·Wanaselja, E.·Yagudayeva, I.·Lee, J.·Vogel, C.·Wichterle, H.·Engle, E.·Mazzoni, E.

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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.

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An, D., Fujiki, R., Iannitelli, D., Smerdon, J., Maity, S., Rose, M., Gelber, A., Wanaselja, E., Yagudayeva, I., Lee, J., Vogel, C., Wichterle, H., Engle, E., Mazzoni, E.. 2019-05-07. Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons. https://doi.org/10.1101/629295

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