Subthalamic nucleus deep brain stimulation alleviates oxidative stress via mitophagy in Parkinson’s disease
Abstract Subthalamic nucleus deep brain stimulation (STN-DBS) has the potential to delay Parkinson’s disease (PD) progression. Whether oxidative stress participates in the neuroprotective effects of DBS and related signaling pathways remains unknown. To address this, we applied STN-DBS to mice and m...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-03-01
|
| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-024-00668-4 |
| _version_ | 1797266847327846400 |
|---|---|
| author | Yingchuan Chen Guanyu Zhu Tianshuo Yuan Ruoyu Ma Xin Zhang Fangang Meng Anchao Yang Tingting Du Jianguo Zhang |
| author_facet | Yingchuan Chen Guanyu Zhu Tianshuo Yuan Ruoyu Ma Xin Zhang Fangang Meng Anchao Yang Tingting Du Jianguo Zhang |
| author_sort | Yingchuan Chen |
| collection | DOAJ |
| description | Abstract Subthalamic nucleus deep brain stimulation (STN-DBS) has the potential to delay Parkinson’s disease (PD) progression. Whether oxidative stress participates in the neuroprotective effects of DBS and related signaling pathways remains unknown. To address this, we applied STN-DBS to mice and monkey models of PD and collected brain tissue to evaluate mitophagy, oxidative stress, and related pathway. To confirm findings in animal experiments, a cohort of PD patients was recruited and oxidative stress was evaluated in cerebrospinal fluid. When PD mice received STN stimulation, the mTOR pathway was suppressed, accompanied by elevated LC3 II expression, increased mitophagosomes, and a decrease in p62 expression. The increase in mitophagy and balance of mitochondrial fission/fusion dynamics in the substantia nigra caused a marked enhancement of the antioxidant enzymes superoxide dismutase and glutathione levels. Subsequently, fewer mitochondrial apoptogenic factors were released to the cytoplasm, which resulted in a suppression of caspase activation and reservation of dopaminergic neurons. While interfaced with an mTOR activator, oxidative stress was no longer regulated by STN-DBS, with no neuroprotective effect. Similar results to those found in the rodent experiments were obtained in monkeys treated with chronic STN stimulation. Moreover, antioxidant enzymes in PD patients were increased after the operation, however, there was no relation between changes in antioxidant enzymes and motor impairment. Collectively, our study found that STN-DBS was able to increase mitophagy via an mTOR-dependent pathway, and oxidative stress was suppressed due to removal of damaged mitochondria, which was attributed to the dopaminergic neuroprotection of STN-DBS in PD. |
| first_indexed | 2024-04-25T01:07:12Z |
| format | Article |
| id | doaj.art-81eb3871b74743529b1cc5d96d2ec91f |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-04-25T01:07:12Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-81eb3871b74743529b1cc5d96d2ec91f2024-03-10T12:08:39ZengNature Portfolionpj Parkinson's Disease2373-80572024-03-0110111510.1038/s41531-024-00668-4Subthalamic nucleus deep brain stimulation alleviates oxidative stress via mitophagy in Parkinson’s diseaseYingchuan Chen0Guanyu Zhu1Tianshuo Yuan2Ruoyu Ma3Xin Zhang4Fangang Meng5Anchao Yang6Tingting Du7Jianguo Zhang8Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityBeijing Key Laboratory of NeurostimulationBeijing Key Laboratory of NeurostimulationDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityBeijing Key Laboratory of NeurostimulationDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityAbstract Subthalamic nucleus deep brain stimulation (STN-DBS) has the potential to delay Parkinson’s disease (PD) progression. Whether oxidative stress participates in the neuroprotective effects of DBS and related signaling pathways remains unknown. To address this, we applied STN-DBS to mice and monkey models of PD and collected brain tissue to evaluate mitophagy, oxidative stress, and related pathway. To confirm findings in animal experiments, a cohort of PD patients was recruited and oxidative stress was evaluated in cerebrospinal fluid. When PD mice received STN stimulation, the mTOR pathway was suppressed, accompanied by elevated LC3 II expression, increased mitophagosomes, and a decrease in p62 expression. The increase in mitophagy and balance of mitochondrial fission/fusion dynamics in the substantia nigra caused a marked enhancement of the antioxidant enzymes superoxide dismutase and glutathione levels. Subsequently, fewer mitochondrial apoptogenic factors were released to the cytoplasm, which resulted in a suppression of caspase activation and reservation of dopaminergic neurons. While interfaced with an mTOR activator, oxidative stress was no longer regulated by STN-DBS, with no neuroprotective effect. Similar results to those found in the rodent experiments were obtained in monkeys treated with chronic STN stimulation. Moreover, antioxidant enzymes in PD patients were increased after the operation, however, there was no relation between changes in antioxidant enzymes and motor impairment. Collectively, our study found that STN-DBS was able to increase mitophagy via an mTOR-dependent pathway, and oxidative stress was suppressed due to removal of damaged mitochondria, which was attributed to the dopaminergic neuroprotection of STN-DBS in PD.https://doi.org/10.1038/s41531-024-00668-4 |
| spellingShingle | Yingchuan Chen Guanyu Zhu Tianshuo Yuan Ruoyu Ma Xin Zhang Fangang Meng Anchao Yang Tingting Du Jianguo Zhang Subthalamic nucleus deep brain stimulation alleviates oxidative stress via mitophagy in Parkinson’s disease npj Parkinson's Disease |
| title | Subthalamic nucleus deep brain stimulation alleviates oxidative stress via mitophagy in Parkinson’s disease |
| title_full | Subthalamic nucleus deep brain stimulation alleviates oxidative stress via mitophagy in Parkinson’s disease |
| title_fullStr | Subthalamic nucleus deep brain stimulation alleviates oxidative stress via mitophagy in Parkinson’s disease |
| title_full_unstemmed | Subthalamic nucleus deep brain stimulation alleviates oxidative stress via mitophagy in Parkinson’s disease |
| title_short | Subthalamic nucleus deep brain stimulation alleviates oxidative stress via mitophagy in Parkinson’s disease |
| title_sort | subthalamic nucleus deep brain stimulation alleviates oxidative stress via mitophagy in parkinson s disease |
| url | https://doi.org/10.1038/s41531-024-00668-4 |
| work_keys_str_mv | AT yingchuanchen subthalamicnucleusdeepbrainstimulationalleviatesoxidativestressviamitophagyinparkinsonsdisease AT guanyuzhu subthalamicnucleusdeepbrainstimulationalleviatesoxidativestressviamitophagyinparkinsonsdisease AT tianshuoyuan subthalamicnucleusdeepbrainstimulationalleviatesoxidativestressviamitophagyinparkinsonsdisease AT ruoyuma subthalamicnucleusdeepbrainstimulationalleviatesoxidativestressviamitophagyinparkinsonsdisease AT xinzhang subthalamicnucleusdeepbrainstimulationalleviatesoxidativestressviamitophagyinparkinsonsdisease AT fangangmeng subthalamicnucleusdeepbrainstimulationalleviatesoxidativestressviamitophagyinparkinsonsdisease AT anchaoyang subthalamicnucleusdeepbrainstimulationalleviatesoxidativestressviamitophagyinparkinsonsdisease AT tingtingdu subthalamicnucleusdeepbrainstimulationalleviatesoxidativestressviamitophagyinparkinsonsdisease AT jianguozhang subthalamicnucleusdeepbrainstimulationalleviatesoxidativestressviamitophagyinparkinsonsdisease |