DDC-Promoter-Driven Chemogenetic Activation of SNpc Dopaminergic Neurons Alleviates Parkinsonian Motor Symptoms
Parkinson’s disease (PD) is a neurodegenerative disorder with typical motor symptoms. Recent studies have suggested that excessive GABA from reactive astrocytes tonically inhibits dopaminergic neurons and reduces the expression of tyrosine hydroxylase (TH), the key dopamine-synthesizing enzyme, in t...
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/2491 |
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| author | Dong-Chan Seo Yeon Ha Ju Jin-Ju Seo Soo-Jin Oh C. Justin Lee Seung Eun Lee Min-Ho Nam |
| author_facet | Dong-Chan Seo Yeon Ha Ju Jin-Ju Seo Soo-Jin Oh C. Justin Lee Seung Eun Lee Min-Ho Nam |
| author_sort | Dong-Chan Seo |
| collection | DOAJ |
| description | Parkinson’s disease (PD) is a neurodegenerative disorder with typical motor symptoms. Recent studies have suggested that excessive GABA from reactive astrocytes tonically inhibits dopaminergic neurons and reduces the expression of tyrosine hydroxylase (TH), the key dopamine-synthesizing enzyme, in the substantia nigra pars compacta (SNpc). However, the expression of DOPA decarboxylase (DDC), another dopamine-synthesizing enzyme, is relatively spared, raising a possibility that the live but non-functional TH-negative/DDC-positive neurons could be the therapeutic target for rescuing PD motor symptoms. However, due to the absence of a validated DDC-specific promoter, manipulating DDC-positive neuronal activity has not been tested as a therapeutic strategy for PD. Here, we developed an AAV vector expressing mCherry under rat DDC promoter (AAV-rDDC-mCherry) and validated the specificity in the rat SNpc. Modifying this vector, we expressed hM3Dq (Gq-DREADD) under DDC promoter in the SNpc and ex vivo electrophysiologically validated the functionality. In the A53T-mutated alpha-synuclein overexpression model of PD, the chemogenetic activation of DDC-positive neurons in the SNpc significantly alleviated the parkinsonian motor symptoms and rescued the nigrostriatal TH expression. Altogether, our DDC-promoter will allow dopaminergic neuron-specific gene delivery in rodents. Furthermore, we propose that the activation of dormant dopaminergic neurons could be a potential therapeutic strategy for PD. |
| first_indexed | 2024-03-11T09:40:53Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:40:53Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6cae44236d58422a8e7581353cdf269d2023-11-16T16:58:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243249110.3390/ijms24032491DDC-Promoter-Driven Chemogenetic Activation of SNpc Dopaminergic Neurons Alleviates Parkinsonian Motor SymptomsDong-Chan Seo0Yeon Ha Ju1Jin-Ju Seo2Soo-Jin Oh3C. Justin Lee4Seung Eun Lee5Min-Ho Nam6Research Animal Resource Center, Korea Institute of Science and Technology (KIST), Seoul 02456, Republic of KoreaBrain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02456, Republic of KoreaResearch Animal Resource Center, Korea Institute of Science and Technology (KIST), Seoul 02456, Republic of KoreaBrain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02456, Republic of KoreaCenter for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of KoreaResearch Animal Resource Center, Korea Institute of Science and Technology (KIST), Seoul 02456, Republic of KoreaBrain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02456, Republic of KoreaParkinson’s disease (PD) is a neurodegenerative disorder with typical motor symptoms. Recent studies have suggested that excessive GABA from reactive astrocytes tonically inhibits dopaminergic neurons and reduces the expression of tyrosine hydroxylase (TH), the key dopamine-synthesizing enzyme, in the substantia nigra pars compacta (SNpc). However, the expression of DOPA decarboxylase (DDC), another dopamine-synthesizing enzyme, is relatively spared, raising a possibility that the live but non-functional TH-negative/DDC-positive neurons could be the therapeutic target for rescuing PD motor symptoms. However, due to the absence of a validated DDC-specific promoter, manipulating DDC-positive neuronal activity has not been tested as a therapeutic strategy for PD. Here, we developed an AAV vector expressing mCherry under rat DDC promoter (AAV-rDDC-mCherry) and validated the specificity in the rat SNpc. Modifying this vector, we expressed hM3Dq (Gq-DREADD) under DDC promoter in the SNpc and ex vivo electrophysiologically validated the functionality. In the A53T-mutated alpha-synuclein overexpression model of PD, the chemogenetic activation of DDC-positive neurons in the SNpc significantly alleviated the parkinsonian motor symptoms and rescued the nigrostriatal TH expression. Altogether, our DDC-promoter will allow dopaminergic neuron-specific gene delivery in rodents. Furthermore, we propose that the activation of dormant dopaminergic neurons could be a potential therapeutic strategy for PD.https://www.mdpi.com/1422-0067/24/3/2491Parkinson’s diseaseDOPA decarboxylasepromoterchemogenetics |
| spellingShingle | Dong-Chan Seo Yeon Ha Ju Jin-Ju Seo Soo-Jin Oh C. Justin Lee Seung Eun Lee Min-Ho Nam DDC-Promoter-Driven Chemogenetic Activation of SNpc Dopaminergic Neurons Alleviates Parkinsonian Motor Symptoms International Journal of Molecular Sciences Parkinson’s disease DOPA decarboxylase promoter chemogenetics |
| title | DDC-Promoter-Driven Chemogenetic Activation of SNpc Dopaminergic Neurons Alleviates Parkinsonian Motor Symptoms |
| title_full | DDC-Promoter-Driven Chemogenetic Activation of SNpc Dopaminergic Neurons Alleviates Parkinsonian Motor Symptoms |
| title_fullStr | DDC-Promoter-Driven Chemogenetic Activation of SNpc Dopaminergic Neurons Alleviates Parkinsonian Motor Symptoms |
| title_full_unstemmed | DDC-Promoter-Driven Chemogenetic Activation of SNpc Dopaminergic Neurons Alleviates Parkinsonian Motor Symptoms |
| title_short | DDC-Promoter-Driven Chemogenetic Activation of SNpc Dopaminergic Neurons Alleviates Parkinsonian Motor Symptoms |
| title_sort | ddc promoter driven chemogenetic activation of snpc dopaminergic neurons alleviates parkinsonian motor symptoms |
| topic | Parkinson’s disease DOPA decarboxylase promoter chemogenetics |
| url | https://www.mdpi.com/1422-0067/24/3/2491 |
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