| Autor: |
Esteban O. Mazzoni, Joun Y. Lee, Shuvadeep Maity, Hynek Wichterle, Elizabeth K. Wanaselja, Disi An, John W. Smerdon, Elizabeth C. Engle, Christine Vogel, Ilona Yagudayeva, Ryosuke Fujiki, Dylan E. Iannitelli |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
SSRN Electronic Journal. |
| ISSN: |
1556-5068 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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