Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons
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 re...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/44423 |
| _version_ | 1818024063209046016 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Disi An |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T03:54:15Z |
| format | Article |
| id | doaj.art-0f4bd1185c1e462d992daccca11bd0d2 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T03:54:15Z |
| publishDate | 2019-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0f4bd1185c1e462d992daccca11bd0d22022-12-22T02:03:10ZengeLife Sciences Publications LtdeLife2050-084X2019-06-01810.7554/eLife.44423Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neuronsDisi An0Ryosuke Fujiki1Dylan E Iannitelli2https://orcid.org/0000-0002-7654-9433John W Smerdon3Shuvadeep Maity4https://orcid.org/0000-0002-6031-4744Matthew F Rose5https://orcid.org/0000-0002-1148-4130Alon Gelber6Elizabeth K Wanaselja7Ilona Yagudayeva8Joun Y Lee9Christine Vogel10https://orcid.org/0000-0002-2856-3118Hynek Wichterle11https://orcid.org/0000-0002-7817-0080Elizabeth C Engle12Esteban Orlando Mazzoni13https://orcid.org/0000-0001-8994-681XDepartment of Biology, New York University, New York, United StatesDepartment 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 StatesDepartment of Biology, New York University, New York, United StatesDepartment of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United StatesDepartment of Biology, New York University, New York, United States; Center for Genomics and Systems Biology, New York University, New York, United StatesDepartment 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 StatesDepartment 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 StatesDepartment of Biology, New York University, New York, United StatesDepartment of Biology, New York University, New York, United StatesDepartment of Neurology, Boston Children’s Hospital, Boston, United States; FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United StatesDepartment of Biology, New York University, New York, United States; Center for Genomics and Systems Biology, New York University, New York, United StatesDepartment of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United StatesDepartment 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 StatesDepartment of Biology, New York University, New York, United States; NYU Neuroscience Institute, NYU Langone Medical Center, New York, United StatesIn 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.https://elifesciences.org/articles/44423stem cell differentiationALSmotor neurons |
| spellingShingle | 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 Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons eLife stem cell differentiation ALS motor neurons |
| title | Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons |
| title_full | Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons |
| title_fullStr | Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons |
| title_full_unstemmed | Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons |
| title_short | Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons |
| title_sort | stem cell derived cranial and spinal motor neurons reveal proteostatic differences between als resistant and sensitive motor neurons |
| topic | stem cell differentiation ALS motor neurons |
| url | https://elifesciences.org/articles/44423 |
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