Parkinson's disease motor symptoms rescue by CRISPRa‐reprogramming astrocytes into GABAergic neurons
Abstract Direct reprogramming based on genetic factors resembles a promising strategy to replace lost cells in degenerative diseases such as Parkinson's disease. For this, we developed a knock‐in mouse line carrying a dual dCas9 transactivator system (dCAM) allowing the conditional in vivo acti...
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114797 |
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| author | Jessica Giehrl‐Schwab Florian Giesert Benedict Rauser Chu Lan Lao Sina Hembach Sandrine Lefort Ignacio L Ibarra Christina Koupourtidou Malte Daniel Luecken Dong‐Jiunn Jeffery Truong Judith Fischer‐Sternjak Giacomo Masserdotti Nilima Prakash Jovica Ninkovic Sabine M Hölter Daniela M Vogt Weisenhorn Fabian J Theis Magdalena Götz Wolfgang Wurst |
| author_facet | Jessica Giehrl‐Schwab Florian Giesert Benedict Rauser Chu Lan Lao Sina Hembach Sandrine Lefort Ignacio L Ibarra Christina Koupourtidou Malte Daniel Luecken Dong‐Jiunn Jeffery Truong Judith Fischer‐Sternjak Giacomo Masserdotti Nilima Prakash Jovica Ninkovic Sabine M Hölter Daniela M Vogt Weisenhorn Fabian J Theis Magdalena Götz Wolfgang Wurst |
| author_sort | Jessica Giehrl‐Schwab |
| collection | DOAJ |
| description | Abstract Direct reprogramming based on genetic factors resembles a promising strategy to replace lost cells in degenerative diseases such as Parkinson's disease. For this, we developed a knock‐in mouse line carrying a dual dCas9 transactivator system (dCAM) allowing the conditional in vivo activation of endogenous genes. To enable a translational application, we additionally established an AAV‐based strategy carrying intein‐split‐dCas9 in combination with activators (AAV‐dCAS). Both approaches were successful in reprogramming striatal astrocytes into induced GABAergic neurons confirmed by single‐cell transcriptome analysis of reprogrammed neurons in vivo. These GABAergic neurons functionally integrate into striatal circuits, alleviating voluntary motor behavior aspects in a 6‐OHDA Parkinson's disease model. Our results suggest a novel intervention strategy beyond the restoration of dopamine levels. Thus, the AAV‐dCAS approach might enable an alternative route for clinical therapies of Parkinson's disease. |
| format | Article |
| id | doaj-art-d6d64f7bdd884a3b9299b97fa956cf9b |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-d6d64f7bdd884a3b9299b97fa956cf9b2025-08-20T04:03:02ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-04-0114512010.15252/emmm.202114797Parkinson's disease motor symptoms rescue by CRISPRa‐reprogramming astrocytes into GABAergic neuronsJessica Giehrl‐Schwab0Florian Giesert1Benedict Rauser2Chu Lan Lao3Sina Hembach4Sandrine Lefort5Ignacio L Ibarra6Christina Koupourtidou7Malte Daniel Luecken8Dong‐Jiunn Jeffery Truong9Judith Fischer‐Sternjak10Giacomo Masserdotti11Nilima Prakash12Jovica Ninkovic13Sabine M Hölter14Daniela M Vogt Weisenhorn15Fabian J Theis16Magdalena Götz17Wolfgang Wurst18Institute of Developmental Genetics, Helmholtz Center MunichInstitute of Developmental Genetics, Helmholtz Center MunichInstitute of Developmental Genetics, Helmholtz Center MunichInstitute of Stem Cell Research, Helmholtz Center MunichInstitute of Developmental Genetics, Helmholtz Center MunichInstitute for Diabetes and Obesity, Helmholtz Center MunichInstitute of Computational Biology, Helmholtz Center MunichInstitute of Stem Cell Research, Helmholtz Center MunichInstitute of Computational Biology, Helmholtz Center MunichInstitute of Developmental Genetics, Helmholtz Center MunichInstitute of Stem Cell Research, Helmholtz Center MunichInstitute of Stem Cell Research, Helmholtz Center MunichLaboratory of Applied Genetics and Stem Cell Biology, Department Hamm 2, Hamm‐Lippstadt University of Applied SciencesInstitute of Stem Cell Research, Helmholtz Center MunichInstitute of Developmental Genetics, Helmholtz Center MunichInstitute of Developmental Genetics, Helmholtz Center MunichInstitute of Computational Biology, Helmholtz Center MunichMunich Cluster for Systems Neurology (SyNergy)Institute of Developmental Genetics, Helmholtz Center MunichAbstract Direct reprogramming based on genetic factors resembles a promising strategy to replace lost cells in degenerative diseases such as Parkinson's disease. For this, we developed a knock‐in mouse line carrying a dual dCas9 transactivator system (dCAM) allowing the conditional in vivo activation of endogenous genes. To enable a translational application, we additionally established an AAV‐based strategy carrying intein‐split‐dCas9 in combination with activators (AAV‐dCAS). Both approaches were successful in reprogramming striatal astrocytes into induced GABAergic neurons confirmed by single‐cell transcriptome analysis of reprogrammed neurons in vivo. These GABAergic neurons functionally integrate into striatal circuits, alleviating voluntary motor behavior aspects in a 6‐OHDA Parkinson's disease model. Our results suggest a novel intervention strategy beyond the restoration of dopamine levels. Thus, the AAV‐dCAS approach might enable an alternative route for clinical therapies of Parkinson's disease.https://doi.org/10.15252/emmm.202114797astrocytesCRISPRaGABAergic neuronsParkinson's diseasereprogramming |
| spellingShingle | Jessica Giehrl‐Schwab Florian Giesert Benedict Rauser Chu Lan Lao Sina Hembach Sandrine Lefort Ignacio L Ibarra Christina Koupourtidou Malte Daniel Luecken Dong‐Jiunn Jeffery Truong Judith Fischer‐Sternjak Giacomo Masserdotti Nilima Prakash Jovica Ninkovic Sabine M Hölter Daniela M Vogt Weisenhorn Fabian J Theis Magdalena Götz Wolfgang Wurst Parkinson's disease motor symptoms rescue by CRISPRa‐reprogramming astrocytes into GABAergic neurons EMBO Molecular Medicine astrocytes CRISPRa GABAergic neurons Parkinson's disease reprogramming |
| title | Parkinson's disease motor symptoms rescue by CRISPRa‐reprogramming astrocytes into GABAergic neurons |
| title_full | Parkinson's disease motor symptoms rescue by CRISPRa‐reprogramming astrocytes into GABAergic neurons |
| title_fullStr | Parkinson's disease motor symptoms rescue by CRISPRa‐reprogramming astrocytes into GABAergic neurons |
| title_full_unstemmed | Parkinson's disease motor symptoms rescue by CRISPRa‐reprogramming astrocytes into GABAergic neurons |
| title_short | Parkinson's disease motor symptoms rescue by CRISPRa‐reprogramming astrocytes into GABAergic neurons |
| title_sort | parkinson s disease motor symptoms rescue by crispra reprogramming astrocytes into gabaergic neurons |
| topic | astrocytes CRISPRa GABAergic neurons Parkinson's disease reprogramming |
| url | https://doi.org/10.15252/emmm.202114797 |
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