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 Mazzoni

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
StatePublished - Jun 3 2019

Fingerprint

Amyotrophic Lateral Sclerosis
Motor Neurons
Stem cells
Neurons
Stem Cells
Embryonic Stem Cells
Proteasome Endopeptidase Complex
Proteome
Chemical activation
Proteins

Keywords

  • ALS
  • motor neurons
  • mouse
  • neuroscience
  • regenerative medicine
  • stem cell differentiation
  • stem cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons. / An, Disi; Fujiki, Ryosuke; Iannitelli, Dylan E.; Smerdon, John W.; Maity, Shuvadeep; Rose, Matthew F.; Gelber, Alon; Wanaselja, Elizabeth K.; Yagudayeva, Ilona; Lee, Joun Y.; Vogel, Christine; Wichterle, Hynek; Engle, Elizabeth C.; Mazzoni, Esteban.

In: eLife, Vol. 8, 03.06.2019.

Research output: Contribution to journalArticle

An, D, Fujiki, R, Iannitelli, DE, Smerdon, JW, Maity, S, Rose, MF, Gelber, A, Wanaselja, EK, Yagudayeva, I, Lee, JY, Vogel, C, Wichterle, H, Engle, EC & Mazzoni, E 2019, 'Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons', eLife, vol. 8. https://doi.org/10.7554/eLife.44423
An, Disi ; Fujiki, Ryosuke ; Iannitelli, Dylan E. ; Smerdon, John W. ; Maity, Shuvadeep ; Rose, Matthew F. ; Gelber, Alon ; Wanaselja, Elizabeth K. ; Yagudayeva, Ilona ; Lee, Joun Y. ; Vogel, Christine ; Wichterle, Hynek ; Engle, Elizabeth C. ; Mazzoni, Esteban. / Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons. In: eLife. 2019 ; Vol. 8.
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