Repressing PTBP1 fails to convert reactive astrocytes to dopaminergic neurons in a 6-hydroxydopamine mouse model of Parkinson’s disease
Lineage reprogramming 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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/75636 |
| _version_ | 1811203418120781824 |
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| author | Weizhao Chen Qiongping Zheng Qiaoying Huang Shanshan Ma Mingtao Li |
| author_facet | Weizhao Chen Qiongping Zheng Qiaoying Huang Shanshan Ma Mingtao Li |
| author_sort | Weizhao Chen |
| collection | DOAJ |
| description | Lineage reprogramming 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 show 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 could 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 confirm that repressing PTBP1 does not convert astrocytes to DAns, regardless of physiological or PD-related pathological conditions. |
| first_indexed | 2024-04-12T02:55:21Z |
| format | Article |
| id | doaj.art-8a7c870e17704528b031b88fce73dbda |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:55:21Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8a7c870e17704528b031b88fce73dbda2022-12-22T03:50:50ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.75636Repressing PTBP1 fails to convert reactive astrocytes to dopaminergic neurons in a 6-hydroxydopamine mouse model of Parkinson’s diseaseWeizhao Chen0https://orcid.org/0000-0002-6753-4854Qiongping Zheng1https://orcid.org/0000-0002-1989-9234Qiaoying Huang2Shanshan Ma3https://orcid.org/0000-0002-3004-9468Mingtao Li4https://orcid.org/0000-0001-5714-9322Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaLineage reprogramming 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 show 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 could 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 confirm that repressing PTBP1 does not convert astrocytes to DAns, regardless of physiological or PD-related pathological conditions.https://elifesciences.org/articles/75636PTBP1astrocyte-to-neuron conversionlineage reprogrammingParkinson's disease6-OHDA modelastrocyte |
| spellingShingle | Weizhao Chen Qiongping Zheng Qiaoying Huang Shanshan Ma Mingtao Li Repressing PTBP1 fails to convert reactive astrocytes to dopaminergic neurons in a 6-hydroxydopamine mouse model of Parkinson’s disease eLife PTBP1 astrocyte-to-neuron conversion lineage reprogramming Parkinson's disease 6-OHDA model astrocyte |
| title | Repressing PTBP1 fails to convert reactive astrocytes to dopaminergic neurons in a 6-hydroxydopamine mouse model of Parkinson’s disease |
| title_full | Repressing PTBP1 fails to convert reactive astrocytes to dopaminergic neurons in a 6-hydroxydopamine mouse model of Parkinson’s disease |
| title_fullStr | Repressing PTBP1 fails to convert reactive astrocytes to dopaminergic neurons in a 6-hydroxydopamine mouse model of Parkinson’s disease |
| title_full_unstemmed | Repressing PTBP1 fails to convert reactive astrocytes to dopaminergic neurons in a 6-hydroxydopamine mouse model of Parkinson’s disease |
| title_short | Repressing PTBP1 fails to convert reactive astrocytes to dopaminergic neurons in a 6-hydroxydopamine mouse model of Parkinson’s disease |
| title_sort | repressing ptbp1 fails to convert reactive astrocytes to dopaminergic neurons in a 6 hydroxydopamine mouse model of parkinson s disease |
| topic | PTBP1 astrocyte-to-neuron conversion lineage reprogramming Parkinson's disease 6-OHDA model astrocyte |
| url | https://elifesciences.org/articles/75636 |
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