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| Status |
Public on Mar 15, 2022 |
| Title |
Rescuing voluntary motor behavior in a Parkinson´s disease model by aCRISPR mediated reprogramming of striatal astrocytes into induced GABAergic neurons |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Cell replacement strategies of affected cells have been performed in clinical studies of Parkinson´s disease with variable outcome. Conversion of endogenous glial cells into functional neurons might represent a more reliable alternative, thus here we developed a knock-in mouse line carrying a dual dCas9 transactivator system (dCAM), which allowed the conditional activation of the endogenous genes Ascl1, Lmx1a, and Nr4a2 in striatal astrocytes in vivo by delivering sgRNAs specific for their endogenous loci. In order to move this successful approach toward translation, we established an AAV based activator system carrying intein-split-dCas9-VP64, SAM (AAV-dCAS) activators, and the specific sgRNAs targeting transcription factor combinations. Both systems, the dCAM and the AAV-dCAS approach were successful in reprogramming of striatal astrocytes into GABAergic neurons, which functionally integrate into striatal circuits as evidenced by the alleviation of specific motor behaviors in a 6-OHDA Parkinson’s disease model. Thus, the AAV-dCAS approach may enable clinical therapies for Parkinson´s disease by reprogramming striatal astrocytes.
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| Overall design |
Examination of cell composition and astrocyte to neuron reprogramming in murine striatal tissue.
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| Contributor(s) |
Giehrl-Schwab J, Giesert F, Rauser B, Lao C, Lefort S, Ibarra IL, Koupourtidou C, Luecken MD, Truong D, Fischer-Sternjak J, Ninkovic J, Hölter SM, Vogt Weisenhorn DM, Theis FJ, Götz M, Wurst W |
| Citation(s) |
35373464 |
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| Submission date |
May 05, 2020 |
| Last update date |
May 25, 2022 |
| Contact name |
Wolfgang Wurst |
| E-mail(s) |
Wurst@helmholtz-muenchen.de
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| Phone |
+498931874110
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| Organization name |
Helmholtz Zentrum München
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| Department |
Institute of Developmental Genetics
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| Street address |
Ingolstaedter Landstrasse 1
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| City |
Neuherberg |
| ZIP/Postal code |
85764 |
| Country |
Germany |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA630398 |
| SRA |
SRP260062 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE149872_RAW.tar |
13.2 Mb |
(http)(custom) |
TAR (of H5AD) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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