eLife (Jun 2019)

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

  • Disi An,
  • Ryosuke Fujiki,
  • Dylan E Iannitelli,
  • John W Smerdon,
  • Shuvadeep Maity,
  • Matthew F Rose,
  • Alon Gelber,
  • Elizabeth K Wanaselja,
  • Ilona Yagudayeva,
  • Joun Y Lee,
  • Christine Vogel,
  • Hynek Wichterle,
  • Elizabeth C Engle,
  • Esteban Orlando Mazzoni

DOI
https://doi.org/10.7554/eLife.44423
Journal volume & issue
Vol. 8

Abstract

Read online

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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