Repressing PTBP1 fails to convert reactive astrocytes to dopaminergic neurons in a 6-hydroxydopamine mouse model of Parkinson's disease
- Sun Yat-sen University, China
Abstract
Lineage reprograming of resident glial cells to dopaminergic neurons (DAns) is an attractive prospect of the cell-replacement therapy for Parkinson's disease (PD). However, it is unclear whether repressing polypyrimidine tract binding protein 1 (PTBP1) could efficiently convert astrocyte to DAns in the substantia nigra and striatum. Although reporter-positive DAns were observed in both groups after delivering the adeno-associated virus (AAV) expressing a reporter with shRNA or CRISPR-CasRx to repress astroglial PTBP1, the possibility of AAV leaking into endogenous DAns could not be excluded without using a reliable lineage-tracing method. By adopting stringent lineage-tracing strategy, two other studies showed that either knockdown or genetic deletion of quiescent astroglial PTBP1 fails to obtain induced DAns under physiological condition. However, the role of reactive astrocytes might be underestimated because upon brain injury, reactive astrocyte can acquire certain stem cell hallmarks that may facilitate the lineage conversion process. Therefore, whether reactive astrocytes could be genuinely converted to DAns after PTBP1 repression in a PD model needs further validation. In this study, we used Aldh1l1-CreERT2-mediated specific astrocyte-lineage-tracing method to investigate whether reactive astrocytes can be converted to DAns in a 6-hydroxydopamine (6-OHDA) mouse model of PD. However, we found that no astrocyte-originated DAn was generated after effective and persistent knockdown of astroglial PTBP1 either in the substantia nigra or in striatum, while AAV 'leakage' to nearby neurons was easily observed. Our results confirmed that repressing PTBP1 does not convert astrocytes to DAns, regardless of physiological or PD-related pathological conditions.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all the Figures.
Article and author information
Author details
Funding
Ministry of Science and Technology of China (the National Key R&D Program of China (2018YFA0108300))
- Mingtao Li
National Natural Science Foundation of China (U1801681,81771368,31871019,32070959)
- Qiaoying Huang
- Shanshan Ma
- Mingtao Li
Department of Science and Technology of Guangdong Province (the Key Realm R&D Program of Guangdong Province (2018B030337001))
- Mingtao Li
Department of Science and Technology of Guangdong Province (the Guangdong Provincial Key Laboratory of Brain Function and Disease (2020B1212060024))
- Mingtao Li
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Serge Przedborski, Columbia University Medical Center, United States
Ethics
Animal experimentation: All animal experiments were approved and performed in strict accordance with the guidelines by the Institutional Animal Care and Use Committee (IACUC) protocols (No.2018-059) of Sun Yat-Sen University, Guangzhou,China.The protocol was reviewed and approved by the Ethics Committee of Zhongshan School of Medicine(ZSSOM) on Laboratory Animal Care(Permit number: SYSU-IACUC-2018-059).All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.
Version history
- Preprint posted: November 15, 2021 (view preprint)
- Received: November 19, 2021
- Accepted: May 6, 2022
- Accepted Manuscript published: May 10, 2022 (version 1)
- Version of Record published: June 20, 2022 (version 2)
Copyright
© 2022, Chen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Repressing PTBP1 fails to convert reactive astrocytes to dopaminergic neurons in a 6-hydroxydopamine mouse model of Parkinson's disease
eLife 11:e75636.
https://doi.org/10.7554/eLife.75636
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