Fbxl18 targets LRRK2 for proteasomal degradation and attenuates cell toxicity
Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of familial Parkinson's disease (PD) and LRRK2 polymorphisms are associated with increased risk for idiopathic PD. However, the molecular mechanisms by which these mutations cause PD remain uncerta...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996116302637 |
| _version_ | 1818610530612412416 |
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| author | Xiaodong Ding Sandeep K. Barodia Lisha Ma Matthew S. Goldberg |
| author_facet | Xiaodong Ding Sandeep K. Barodia Lisha Ma Matthew S. Goldberg |
| author_sort | Xiaodong Ding |
| collection | DOAJ |
| description | Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of familial Parkinson's disease (PD) and LRRK2 polymorphisms are associated with increased risk for idiopathic PD. However, the molecular mechanisms by which these mutations cause PD remain uncertain. In vitro studies indicate that disease-linked mutations in LRRK2 increase LRRK2 kinase activity and LRRK2-mediated cell toxicity. Identifying LRRK2-interacting proteins and determining their effects on LRRK2 are important for understanding LRRK2 function and for delineating the pathophysiological mechanisms of LRRK2 mutations. Here we identified a novel protein, F-box and leucine-rich repeat domain-containing protein 18 (Fbxl18) that physically associates with LRRK2. We demonstrated that Fbxl18 is a component of a Skp1-Cullin1-F-box ubiquitin ligase complex that regulates the abundance of LRRK2 by selectively targeting phosphorylated LRRK2 for ubiquitination and proteasomal degradation. Knockdown of endogenous Fbxl18 stabilized LRRK2 abundance while protein kinase C activation enhanced LRRK2 degradation by Fbxl18. Dephosphorylation of LRRK2 blocked Fbxl18 association with LRRK2. Taken together, we have identified potential mechanisms for LRRK2 regulation by kinase signaling pathways. Furthermore, Fbxl18 prevented caspase activation and cell death caused by LRRK2 and PD-linked mutant LRRK2. This reveals novel targets for developing potential therapies for familial and idiopathic PD. |
| first_indexed | 2024-12-16T15:15:54Z |
| format | Article |
| id | doaj.art-468c4088f8f14fbea1e63a68bc53eac9 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T15:15:54Z |
| publishDate | 2017-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-468c4088f8f14fbea1e63a68bc53eac92022-12-21T22:26:47ZengElsevierNeurobiology of Disease1095-953X2017-02-0198122136Fbxl18 targets LRRK2 for proteasomal degradation and attenuates cell toxicityXiaodong Ding0Sandeep K. Barodia1Lisha Ma2Matthew S. Goldberg3Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USACenter for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, USADepartment of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USADepartment of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA; Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, USA; Corresponding author at: Department of Neurology, University of Alabama at Birmingham, 1720 2nd Ave South, Birmingham, AL 35294, USA.Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of familial Parkinson's disease (PD) and LRRK2 polymorphisms are associated with increased risk for idiopathic PD. However, the molecular mechanisms by which these mutations cause PD remain uncertain. In vitro studies indicate that disease-linked mutations in LRRK2 increase LRRK2 kinase activity and LRRK2-mediated cell toxicity. Identifying LRRK2-interacting proteins and determining their effects on LRRK2 are important for understanding LRRK2 function and for delineating the pathophysiological mechanisms of LRRK2 mutations. Here we identified a novel protein, F-box and leucine-rich repeat domain-containing protein 18 (Fbxl18) that physically associates with LRRK2. We demonstrated that Fbxl18 is a component of a Skp1-Cullin1-F-box ubiquitin ligase complex that regulates the abundance of LRRK2 by selectively targeting phosphorylated LRRK2 for ubiquitination and proteasomal degradation. Knockdown of endogenous Fbxl18 stabilized LRRK2 abundance while protein kinase C activation enhanced LRRK2 degradation by Fbxl18. Dephosphorylation of LRRK2 blocked Fbxl18 association with LRRK2. Taken together, we have identified potential mechanisms for LRRK2 regulation by kinase signaling pathways. Furthermore, Fbxl18 prevented caspase activation and cell death caused by LRRK2 and PD-linked mutant LRRK2. This reveals novel targets for developing potential therapies for familial and idiopathic PD.http://www.sciencedirect.com/science/article/pii/S0969996116302637LRRK2KinaseCell death |
| spellingShingle | Xiaodong Ding Sandeep K. Barodia Lisha Ma Matthew S. Goldberg Fbxl18 targets LRRK2 for proteasomal degradation and attenuates cell toxicity Neurobiology of Disease LRRK2 Kinase Cell death |
| title | Fbxl18 targets LRRK2 for proteasomal degradation and attenuates cell toxicity |
| title_full | Fbxl18 targets LRRK2 for proteasomal degradation and attenuates cell toxicity |
| title_fullStr | Fbxl18 targets LRRK2 for proteasomal degradation and attenuates cell toxicity |
| title_full_unstemmed | Fbxl18 targets LRRK2 for proteasomal degradation and attenuates cell toxicity |
| title_short | Fbxl18 targets LRRK2 for proteasomal degradation and attenuates cell toxicity |
| title_sort | fbxl18 targets lrrk2 for proteasomal degradation and attenuates cell toxicity |
| topic | LRRK2 Kinase Cell death |
| url | http://www.sciencedirect.com/science/article/pii/S0969996116302637 |
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