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

53 Pages Posted: 10 Sep 2018 Sneak Peek Status: Review Complete

See all articles by Disi An

Disi An

New York University (NYU) - Department of Biology

Ryosuke Fujiki

Boston Children’s Hospital - Department of Neurology

John W. Smerdon

Columbia University - Department of Physiology and Cellular Biophysics

Dylan E. Iannitelli

New York University (NYU) - Department of Biology

Elizabeth K. Wanaselja

New York University (NYU) - Department of Biology

Ilona Yagudayeva

New York University (NYU) - Department of Biology

Joun Y. Lee

Boston Children’s Hospital - Department of Neurology

Shuvadeep Maity

New York University (NYU) - Department of Biology

Christine Vogel

New York University (NYU) - Center for Genomics and Systems Biology

Hynek Wichterle

Columbia University - Department of Physiology and Cellular Biophysics

Elizabeth C. Engle

Boston Children’s Hospital - Department of Neurology

Esteban O. Mazzoni

New York University (NYU) - Department of Biology

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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 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.

Suggested Citation

An, Disi and Fujiki, Ryosuke and Smerdon, John W. and Iannitelli, Dylan E. and Wanaselja, Elizabeth K. and Yagudayeva, Ilona and Lee, Joun Y. and Maity, Shuvadeep and Vogel, Christine and Wichterle, Hynek and Engle, Elizabeth C. and Mazzoni, Esteban O., Stem Cell-Derived Cranial and Spinal Motor Neurons Reveal Proteostatic Differences between ALS Resistant and Sensitive Motor Neurons (September 6, 2018). Available at SSRN: https://ssrn.com/abstract=3246042 or http://dx.doi.org/10.2139/ssrn.3246042
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Disi An (Contact Author)

New York University (NYU) - Department of Biology

100 Washington Square East
Room 1009
New York, NY 10003-6688
United States

Ryosuke Fujiki

Boston Children’s Hospital - Department of Neurology

300 Longwood Avenue
Boston, MA 02115
United States

John W. Smerdon

Columbia University - Department of Physiology and Cellular Biophysics

1150 St. Nicholas Ave., Room 508
Russ Berrie Pavilion
New York, NY 10032
United States

Dylan E. Iannitelli

New York University (NYU) - Department of Biology

100 Washington Square East
Room 1009
New York, NY 10003-6688
United States

Elizabeth K. Wanaselja

New York University (NYU) - Department of Biology

100 Washington Square East
Room 1009
New York, NY 10003-6688
United States

Ilona Yagudayeva

New York University (NYU) - Department of Biology

100 Washington Square East
Room 1009
New York, NY 10003-6688
United States

Joun Y. Lee

Boston Children’s Hospital - Department of Neurology

300 Longwood Avenue
Boston, MA 02115
United States

Shuvadeep Maity

New York University (NYU) - Department of Biology

100 Washington Square East
Room 1009
New York, NY 10003-6688
United States

Christine Vogel

New York University (NYU) - Center for Genomics and Systems Biology ( email )

New York, NY
United States

Hynek Wichterle

Columbia University - Department of Physiology and Cellular Biophysics

3022 Broadway
New York, NY 10027
United States

Elizabeth C. Engle

Boston Children’s Hospital - Department of Neurology

300 Longwood Avenue
Boston, MA 02115
United States

Esteban O. Mazzoni

New York University (NYU) - Department of Biology ( email )

100 Washington Square East
Room 1009
New York, NY 10003-6688
United States

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