LRRK2 Gly2019Ser Mutation Promotes ER Stress via Interacting with THBS1/TGF‐β1 in Parkinson's Disease
Abstract The gene mutations of LRRK2, which encodes leucine‐rich repeat kinase 2 (LRRK2), are associated with one of the most prevalent monogenic forms of Parkinson's disease (PD). However, the potential effectors of the Gly2019Ser (G2019S) mutation remain unknown. In this study, the authors in...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-10-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202303711 |
| _version_ | 1827782626947104768 |
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| author | Longping Yao Fengfei Lu Sumeyye Koc Zijian Zheng Baoyan Wang Shizhong Zhang Thomas Skutella Guohui Lu |
| author_facet | Longping Yao Fengfei Lu Sumeyye Koc Zijian Zheng Baoyan Wang Shizhong Zhang Thomas Skutella Guohui Lu |
| author_sort | Longping Yao |
| collection | DOAJ |
| description | Abstract The gene mutations of LRRK2, which encodes leucine‐rich repeat kinase 2 (LRRK2), are associated with one of the most prevalent monogenic forms of Parkinson's disease (PD). However, the potential effectors of the Gly2019Ser (G2019S) mutation remain unknown. In this study, the authors investigate the effects of LRRK2 G2019S on endoplasmic reticulum (ER) stress in induced pluripotent stem cell (iPSC)‐induced dopamine neurons and explore potential therapeutic targets in mice model. These findings demonstrate that LRRK2 G2019S significantly promotes ER stress in neurons and mice. Interestingly, inhibiting LRRK2 activity can ameliorate ER stress induced by the mutation. Moreover, LRRK2 mutation can induce ER stress by directly interacting with thrombospondin‐1/transforming growth factor beta1 (THBS1/TGF‐β1). Inhibition of LRRK2 kinase activity can effectively suppress ER stress and the expression of THBS1/TGF‐β1. Knocking down THBS1 can rescue ER stress by interacting with TGF‐β1 and behavior burden caused by the LRRK2 mutation, while suppression of TGF‐β1 has a similar effect. Overall, it is demonstrated that the LRRK2 mutation promotes ER stress by directly interacting with THBS1/TGF‐β1, leading to neural death in PD. These findings provide valuable insights into the pathogenesis of PD, highlighting potential diagnostic markers and therapeutic targets. |
| first_indexed | 2024-03-11T15:35:35Z |
| format | Article |
| id | doaj.art-ef23487a7cac4e8ab1f212f9965210d8 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-11T15:35:35Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-ef23487a7cac4e8ab1f212f9965210d82023-10-26T20:10:12ZengWileyAdvanced Science2198-38442023-10-011030n/an/a10.1002/advs.202303711LRRK2 Gly2019Ser Mutation Promotes ER Stress via Interacting with THBS1/TGF‐β1 in Parkinson's DiseaseLongping Yao0Fengfei Lu1Sumeyye Koc2Zijian Zheng3Baoyan Wang4Shizhong Zhang5Thomas Skutella6Guohui Lu7Department of Neurosurgery First Affiliated Hospital of Nanchang University Nanchang 330209 P. R. ChinaDepartment of Neurosurgery Zhujiang Hospital Southern Medical University Guangzhou 510282 P. R. ChinaDepartment of Neuroscience Institute of Health Sciences Ondokuz Mayıs University Samsun 55139 TurkeyDepartment of Neurosurgery First Affiliated Hospital of Nanchang University Nanchang 330209 P. R. ChinaDepartment of Neurosurgery Zhujiang Hospital Southern Medical University Guangzhou 510282 P. R. ChinaDepartment of Neurosurgery Zhujiang Hospital Southern Medical University Guangzhou 510282 P. R. ChinaInstitute for Anatomy and Cell Biology Medical Faculty Heidelberg University 69120 Heidelberg GermanyDepartment of Neurosurgery First Affiliated Hospital of Nanchang University Nanchang 330209 P. R. ChinaAbstract The gene mutations of LRRK2, which encodes leucine‐rich repeat kinase 2 (LRRK2), are associated with one of the most prevalent monogenic forms of Parkinson's disease (PD). However, the potential effectors of the Gly2019Ser (G2019S) mutation remain unknown. In this study, the authors investigate the effects of LRRK2 G2019S on endoplasmic reticulum (ER) stress in induced pluripotent stem cell (iPSC)‐induced dopamine neurons and explore potential therapeutic targets in mice model. These findings demonstrate that LRRK2 G2019S significantly promotes ER stress in neurons and mice. Interestingly, inhibiting LRRK2 activity can ameliorate ER stress induced by the mutation. Moreover, LRRK2 mutation can induce ER stress by directly interacting with thrombospondin‐1/transforming growth factor beta1 (THBS1/TGF‐β1). Inhibition of LRRK2 kinase activity can effectively suppress ER stress and the expression of THBS1/TGF‐β1. Knocking down THBS1 can rescue ER stress by interacting with TGF‐β1 and behavior burden caused by the LRRK2 mutation, while suppression of TGF‐β1 has a similar effect. Overall, it is demonstrated that the LRRK2 mutation promotes ER stress by directly interacting with THBS1/TGF‐β1, leading to neural death in PD. These findings provide valuable insights into the pathogenesis of PD, highlighting potential diagnostic markers and therapeutic targets.https://doi.org/10.1002/advs.202303711endoplasmic reticulum (ER) stressLRRK2 G2019SParkinson's diseaseTGF‐β1THBS1 |
| spellingShingle | Longping Yao Fengfei Lu Sumeyye Koc Zijian Zheng Baoyan Wang Shizhong Zhang Thomas Skutella Guohui Lu LRRK2 Gly2019Ser Mutation Promotes ER Stress via Interacting with THBS1/TGF‐β1 in Parkinson's Disease Advanced Science endoplasmic reticulum (ER) stress LRRK2 G2019S Parkinson's disease TGF‐β1 THBS1 |
| title | LRRK2 Gly2019Ser Mutation Promotes ER Stress via Interacting with THBS1/TGF‐β1 in Parkinson's Disease |
| title_full | LRRK2 Gly2019Ser Mutation Promotes ER Stress via Interacting with THBS1/TGF‐β1 in Parkinson's Disease |
| title_fullStr | LRRK2 Gly2019Ser Mutation Promotes ER Stress via Interacting with THBS1/TGF‐β1 in Parkinson's Disease |
| title_full_unstemmed | LRRK2 Gly2019Ser Mutation Promotes ER Stress via Interacting with THBS1/TGF‐β1 in Parkinson's Disease |
| title_short | LRRK2 Gly2019Ser Mutation Promotes ER Stress via Interacting with THBS1/TGF‐β1 in Parkinson's Disease |
| title_sort | lrrk2 gly2019ser mutation promotes er stress via interacting with thbs1 tgf β1 in parkinson s disease |
| topic | endoplasmic reticulum (ER) stress LRRK2 G2019S Parkinson's disease TGF‐β1 THBS1 |
| url | https://doi.org/10.1002/advs.202303711 |
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