Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by the loss of the upper and lower motor neurons. Approximately 10% of cases are caused by specific mutations in known genes, with the remaining cases having no known genetic link. As such, sporadic cases have...
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| Format: | Article |
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MDPI AG
2020-02-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/3/571 |
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| author | Emily R. Seminary Stephanie Santarriaga Lynn Wheeler Marie Mejaki Jenica Abrudan Wendy Demos Michael T. Zimmermann Raul A. Urrutia Dominic Fee Paul E. Barkhaus Allison D. Ebert |
| author_facet | Emily R. Seminary Stephanie Santarriaga Lynn Wheeler Marie Mejaki Jenica Abrudan Wendy Demos Michael T. Zimmermann Raul A. Urrutia Dominic Fee Paul E. Barkhaus Allison D. Ebert |
| author_sort | Emily R. Seminary |
| collection | DOAJ |
| description | Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by the loss of the upper and lower motor neurons. Approximately 10% of cases are caused by specific mutations in known genes, with the remaining cases having no known genetic link. As such, sporadic cases have been more difficult to model experimentally. Here, we describe the generation and differentiation of ALS induced pluripotent stem cells reprogrammed from discordant identical twins. Whole genome sequencing revealed no relevant mutations in known ALS-causing genes that differ between the twins. As protein aggregation is found in all ALS patients and is thought to contribute to motor neuron death, we sought to characterize the aggregation phenotype of the sporadic ALS induced pluripotent stem cells (iPSCs). Motor neurons from both twins had high levels of insoluble proteins that commonly aggregate in ALS that did not robustly change in response to exogenous glutamate. In contrast, established genetic ALS iPSC lines demonstrated insolubility in a protein- and genotype-dependent manner. Moreover, whereas the genetic ALS lines failed to induce autophagy after glutamate stress, motor neurons from both twins and independent controls did activate this protective pathway. Together, these data indicate that our unique model of sporadic ALS may provide key insights into disease pathology and highlight potential differences between sporadic and familial ALS. |
| first_indexed | 2024-03-12T09:39:44Z |
| format | Article |
| id | doaj.art-093317604a7548b89da66bc393e6a3f4 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T09:39:44Z |
| publishDate | 2020-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-093317604a7548b89da66bc393e6a3f42023-09-02T13:19:52ZengMDPI AGCells2073-44092020-02-019357110.3390/cells9030571cells9030571Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral SclerosisEmily R. Seminary0Stephanie Santarriaga1Lynn Wheeler2Marie Mejaki3Jenica Abrudan4Wendy Demos5Michael T. Zimmermann6Raul A. Urrutia7Dominic Fee8Paul E. Barkhaus9Allison D. Ebert10Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Neurology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Neurology, Medical College of Wisconsin, Milwaukee, WI 53226, USABioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USABioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USABioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USABioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Neurology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Neurology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USAAmyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by the loss of the upper and lower motor neurons. Approximately 10% of cases are caused by specific mutations in known genes, with the remaining cases having no known genetic link. As such, sporadic cases have been more difficult to model experimentally. Here, we describe the generation and differentiation of ALS induced pluripotent stem cells reprogrammed from discordant identical twins. Whole genome sequencing revealed no relevant mutations in known ALS-causing genes that differ between the twins. As protein aggregation is found in all ALS patients and is thought to contribute to motor neuron death, we sought to characterize the aggregation phenotype of the sporadic ALS induced pluripotent stem cells (iPSCs). Motor neurons from both twins had high levels of insoluble proteins that commonly aggregate in ALS that did not robustly change in response to exogenous glutamate. In contrast, established genetic ALS iPSC lines demonstrated insolubility in a protein- and genotype-dependent manner. Moreover, whereas the genetic ALS lines failed to induce autophagy after glutamate stress, motor neurons from both twins and independent controls did activate this protective pathway. Together, these data indicate that our unique model of sporadic ALS may provide key insights into disease pathology and highlight potential differences between sporadic and familial ALS.https://www.mdpi.com/2073-4409/9/3/571induced pluripotent stem cellsprotein aggregationglutamate toxicitysod1c9orf72sporadic alsfamilial als |
| spellingShingle | Emily R. Seminary Stephanie Santarriaga Lynn Wheeler Marie Mejaki Jenica Abrudan Wendy Demos Michael T. Zimmermann Raul A. Urrutia Dominic Fee Paul E. Barkhaus Allison D. Ebert Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis Cells induced pluripotent stem cells protein aggregation glutamate toxicity sod1 c9orf72 sporadic als familial als |
| title | Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis |
| title_full | Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis |
| title_fullStr | Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis |
| title_full_unstemmed | Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis |
| title_short | Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis |
| title_sort | motor neuron generation from ipscs from identical twins discordant for amyotrophic lateral sclerosis |
| topic | induced pluripotent stem cells protein aggregation glutamate toxicity sod1 c9orf72 sporadic als familial als |
| url | https://www.mdpi.com/2073-4409/9/3/571 |
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