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

eLife

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[1] Department of Biology, New York University, New York, United States;Department of Biology, New York University, New York, United States;Center for Genomics and Systems Biology, New York University, New York, United States;Department of Biology, New York University, New York, United States;NYU Neuroscience Institute, NYU Langone Medical Center, New York, United States;Department of Neurology, Boston Children’s Hospital, Boston, United States;FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States;Department of Neurology, Boston Children’s Hospital, Boston, United States;FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States;Broad Institute of MIT and Harvard, Cambridge, United States;Department of Neurology, Boston Children’s Hospital, Boston, United States;FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States;Department of Neurology, Harvard Medical School, Boston, United States;Medical Genetics Training Program, Harvard Medical School, Boston, United States;Department of Neurology, Boston Children’s Hospital, Boston, United States;FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States;Department of Neurology, Harvard Medical School, Boston, United States;Medical Genetics Training Program, Harvard Medical School, Boston, United States;Broad Institute of MIT and Harvard, Cambridge, United States;Howard Hughes Medical Institute, Chevy Chase, United States;Department of Ophthalmology, Boston Children’s Hospital, Boston, United States;Department of Ophthalmology, Harvard Medical School, Boston, United States;Department of Neurology, Boston Children’s Hospital, Boston, United States;FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States;Medical Genetics Training Program, Harvard Medical School, Boston, United States;Department of Pathology, Brigham and Women’s Hospital, Boston, United States;Department of Pathology, Boston Children’s Hospital, Boston, United States;Department of Pathology, Harvard Medical School, Boston, United States;Broad Institute of MIT and Harvard, Cambridge, United States;Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States;

关键词: stem cell differentiation;    ALS;    motor neurons;    Mouse;   

DOI  :  10.7554/eLife.44423

来源: publisher

【 摘 要 】

10.7554/eLife.44423.001In 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.

【 授权许可】

CC BY