Disruption of axonal transport in Parkinson’s disease: the role of pathological α-Syn and AMPK/p38 MAPK signaling
Abstract The accumulation of α-synuclein within Lewy bodies is a critical factor in the pathogenesis of Parkinson’s disease, with potential implications for axonal transport deficits. Activated asparagine endopeptidase enzymatically cleaves α-synuclein and tau, resulting in the formation of α-SynN10...
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| Format: | Article |
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Nature Portfolio
2025-05-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-025-00926-z |
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| author | Xiaoman Yang Zhuoran Ma Piaopiao Lian Yi Wu Ke Liu Zhaoyuan Zhang Zhicheng Tang Yan Xu Xuebing Cao |
| author_facet | Xiaoman Yang Zhuoran Ma Piaopiao Lian Yi Wu Ke Liu Zhaoyuan Zhang Zhicheng Tang Yan Xu Xuebing Cao |
| author_sort | Xiaoman Yang |
| collection | DOAJ |
| description | Abstract The accumulation of α-synuclein within Lewy bodies is a critical factor in the pathogenesis of Parkinson’s disease, with potential implications for axonal transport deficits. Activated asparagine endopeptidase enzymatically cleaves α-synuclein and tau, resulting in the formation of α-SynN103 and tauN368, which are markedly elevated in the brains with Parkinson’s disease. In this study, rats received intrastriatal injections of 15 µg of preformed α-SynN103 and tauN368 fibrils, and their behaviors were evaluated after a 2-month period. Subsequent analyses investigated alterations in axonal transport and the underlying molecular mechanisms. Our findings indicated that preformed fibrils reduced kinesin levels and excessively activated the AMPK and p38 MAPK, thereby compromising the function of kinesin and dynein in axonal transport. Pharmacological inhibition of AMPK and p38 MAPK ameliorated these dysfunctions in rat models, which identified Compound C and SB203580 as potent inhibitors, offering evidence for early interventions of Parkinson’s disease. Mechanisms by which PFFs caused axonal transport defects of dopamine neurons in PD-like models. (A) Shows normal axonal transport. (B) Demonstrates how PFFs increase ?-Syn accumulation, reducing PIKE expression and triggering AMPK/p38 MAPK over-activation, which lowers kinesin levels and motor-cargo interaction. (C) AMPK activity inhibition with C.C significantly improves these deficits. (D) The p38 inhibitor enhances kinesin transport by preventing p38 MAPK over-activation, reducing its inhibition of kinesin-cargo binding. |
| format | Article |
| id | doaj-art-d4fe2b514ff141feb9850e20a7873672 |
| institution | OA Journals |
| issn | 2373-8057 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj-art-d4fe2b514ff141feb9850e20a78736722025-08-20T02:15:00ZengNature Portfolionpj Parkinson's Disease2373-80572025-05-0111111610.1038/s41531-025-00926-zDisruption of axonal transport in Parkinson’s disease: the role of pathological α-Syn and AMPK/p38 MAPK signalingXiaoman Yang0Zhuoran Ma1Piaopiao Lian2Yi Wu3Ke Liu4Zhaoyuan Zhang5Zhicheng Tang6Yan Xu7Xuebing Cao8Department of Neurology, Renmin Hospital of Wuhan UniversityDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract The accumulation of α-synuclein within Lewy bodies is a critical factor in the pathogenesis of Parkinson’s disease, with potential implications for axonal transport deficits. Activated asparagine endopeptidase enzymatically cleaves α-synuclein and tau, resulting in the formation of α-SynN103 and tauN368, which are markedly elevated in the brains with Parkinson’s disease. In this study, rats received intrastriatal injections of 15 µg of preformed α-SynN103 and tauN368 fibrils, and their behaviors were evaluated after a 2-month period. Subsequent analyses investigated alterations in axonal transport and the underlying molecular mechanisms. Our findings indicated that preformed fibrils reduced kinesin levels and excessively activated the AMPK and p38 MAPK, thereby compromising the function of kinesin and dynein in axonal transport. Pharmacological inhibition of AMPK and p38 MAPK ameliorated these dysfunctions in rat models, which identified Compound C and SB203580 as potent inhibitors, offering evidence for early interventions of Parkinson’s disease. Mechanisms by which PFFs caused axonal transport defects of dopamine neurons in PD-like models. (A) Shows normal axonal transport. (B) Demonstrates how PFFs increase ?-Syn accumulation, reducing PIKE expression and triggering AMPK/p38 MAPK over-activation, which lowers kinesin levels and motor-cargo interaction. (C) AMPK activity inhibition with C.C significantly improves these deficits. (D) The p38 inhibitor enhances kinesin transport by preventing p38 MAPK over-activation, reducing its inhibition of kinesin-cargo binding.https://doi.org/10.1038/s41531-025-00926-z |
| spellingShingle | Xiaoman Yang Zhuoran Ma Piaopiao Lian Yi Wu Ke Liu Zhaoyuan Zhang Zhicheng Tang Yan Xu Xuebing Cao Disruption of axonal transport in Parkinson’s disease: the role of pathological α-Syn and AMPK/p38 MAPK signaling npj Parkinson's Disease |
| title | Disruption of axonal transport in Parkinson’s disease: the role of pathological α-Syn and AMPK/p38 MAPK signaling |
| title_full | Disruption of axonal transport in Parkinson’s disease: the role of pathological α-Syn and AMPK/p38 MAPK signaling |
| title_fullStr | Disruption of axonal transport in Parkinson’s disease: the role of pathological α-Syn and AMPK/p38 MAPK signaling |
| title_full_unstemmed | Disruption of axonal transport in Parkinson’s disease: the role of pathological α-Syn and AMPK/p38 MAPK signaling |
| title_short | Disruption of axonal transport in Parkinson’s disease: the role of pathological α-Syn and AMPK/p38 MAPK signaling |
| title_sort | disruption of axonal transport in parkinson s disease the role of pathological α syn and ampk p38 mapk signaling |
| url | https://doi.org/10.1038/s41531-025-00926-z |
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