Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain
Abstract Background Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson’s disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocytes in idiopathic PD, as well as incr...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-01-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13024-021-00509-5 |
| _version_ | 1798026498389573632 |
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| author | Enquan Xu Ravindra Boddu Hisham A. Abdelmotilib Arpine Sokratian Kaela Kelly Zhiyong Liu Nicole Bryant Sidhanth Chandra Samantha M. Carlisle Elliot J. Lefkowitz Ashley S. Harms Etty N. Benveniste Talene A. Yacoubian Laura A. Volpicelli-Daley David G. Standaert Andrew B. West |
| author_facet | Enquan Xu Ravindra Boddu Hisham A. Abdelmotilib Arpine Sokratian Kaela Kelly Zhiyong Liu Nicole Bryant Sidhanth Chandra Samantha M. Carlisle Elliot J. Lefkowitz Ashley S. Harms Etty N. Benveniste Talene A. Yacoubian Laura A. Volpicelli-Daley David G. Standaert Andrew B. West |
| author_sort | Enquan Xu |
| collection | DOAJ |
| description | Abstract Background Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson’s disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocytes in idiopathic PD, as well as increased phosphorylation of the LRRK2 kinase substrate Rab10 in monocytes in some LRRK2 mutation carriers. Brain-engrafting pro-inflammatory monocytes have been implicated in dopaminergic neurodegeneration in PD models. Here we examine how α-synuclein and LRRK2 interact in monocytes and subsequent neuroinflammatory responses. Methods Human and mouse monocytes were differentiated to distinct transcriptional states resembling macrophages, dendritic cells, or microglia, and exposed to well-characterized human or mouse α-synuclein fibrils. LRRK2 expression and LRRK2-dependent Rab10 phosphorylation were measured with monoclonal antibodies, and myeloid cell responses to α-synuclein fibrils in R1441C-Lrrk2 knock-in mice or G2019S-Lrrk2 BAC mice were evaluated by flow cytometry. Chemotaxis assays were performed with monocyte-derived macrophages stimulated with α-synuclein fibrils and microglia in Boyden chambers. Results α-synuclein fibrils robustly stimulate LRRK2 and Rab10 phosphorylation in human and mouse macrophages and dendritic-like cells. In these cells, α-synuclein fibrils stimulate LRRK2 through JAK-STAT activation and intrinsic LRRK2 kinase activity in a feed-forward pathway that upregulates phosphorylated Rab10. In contrast, LRRK2 expression and Rab10 phosphorylation are both suppressed in microglia-like cells that are otherwise highly responsive to α-synuclein fibrils. Corroborating these results, LRRK2 expression in the brain parenchyma occurs in pro-inflammatory monocytes infiltrating from the periphery, distinct from brain-resident microglia. Mice expressing pathogenic LRRK2 mutations G2019S or R1441C have increased numbers of infiltrating pro-inflammatory monocytes in acute response to α-synuclein fibrils. In primary cultured macrophages, LRRK2 kinase inhibition dampens α-synuclein fibril and microglia-stimulated chemotaxis. Conclusions Pathologic α-synuclein activates LRRK2 expression and kinase activity in monocytes and induces their recruitment to the brain. These results predict that LRRK2 kinase inhibition may attenuate damaging pro-inflammatory monocyte responses in the brain. |
| first_indexed | 2024-04-11T18:37:32Z |
| format | Article |
| id | doaj.art-650263aba80f4a2ebcfa23775edbadc2 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-04-11T18:37:32Z |
| publishDate | 2022-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-650263aba80f4a2ebcfa23775edbadc22022-12-22T04:09:13ZengBMCMolecular Neurodegeneration1750-13262022-01-0117111910.1186/s13024-021-00509-5Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brainEnquan Xu0Ravindra Boddu1Hisham A. Abdelmotilib2Arpine Sokratian3Kaela Kelly4Zhiyong Liu5Nicole Bryant6Sidhanth Chandra7Samantha M. Carlisle8Elliot J. Lefkowitz9Ashley S. Harms10Etty N. Benveniste11Talene A. Yacoubian12Laura A. Volpicelli-Daley13David G. Standaert14Andrew B. West15Duke Center for Neurodegeneration Research, Duke UniversityDuke Center for Neurodegeneration Research, Duke UniversityDepartment of Neurology, University of IowaDuke Center for Neurodegeneration Research, Duke UniversityDuke Center for Neurodegeneration Research, Duke UniversityDuke Center for Neurodegeneration Research, Duke UniversityDuke Center for Neurodegeneration Research, Duke UniversityMedical Scientist Training Program, Northwestern University Feinberg School of MedicineCenter for Clinical and Translational Science, University of Alabama at BirminghamDepartment of Microbiology, University of Alabama at BirminghamCenter for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at BirminghamDepartment of Cell, Developmental and Integrative Biology, University of Alabama at BirminghamCenter for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at BirminghamCenter for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at BirminghamCenter for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at BirminghamDuke Center for Neurodegeneration Research, Duke UniversityAbstract Background Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson’s disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocytes in idiopathic PD, as well as increased phosphorylation of the LRRK2 kinase substrate Rab10 in monocytes in some LRRK2 mutation carriers. Brain-engrafting pro-inflammatory monocytes have been implicated in dopaminergic neurodegeneration in PD models. Here we examine how α-synuclein and LRRK2 interact in monocytes and subsequent neuroinflammatory responses. Methods Human and mouse monocytes were differentiated to distinct transcriptional states resembling macrophages, dendritic cells, or microglia, and exposed to well-characterized human or mouse α-synuclein fibrils. LRRK2 expression and LRRK2-dependent Rab10 phosphorylation were measured with monoclonal antibodies, and myeloid cell responses to α-synuclein fibrils in R1441C-Lrrk2 knock-in mice or G2019S-Lrrk2 BAC mice were evaluated by flow cytometry. Chemotaxis assays were performed with monocyte-derived macrophages stimulated with α-synuclein fibrils and microglia in Boyden chambers. Results α-synuclein fibrils robustly stimulate LRRK2 and Rab10 phosphorylation in human and mouse macrophages and dendritic-like cells. In these cells, α-synuclein fibrils stimulate LRRK2 through JAK-STAT activation and intrinsic LRRK2 kinase activity in a feed-forward pathway that upregulates phosphorylated Rab10. In contrast, LRRK2 expression and Rab10 phosphorylation are both suppressed in microglia-like cells that are otherwise highly responsive to α-synuclein fibrils. Corroborating these results, LRRK2 expression in the brain parenchyma occurs in pro-inflammatory monocytes infiltrating from the periphery, distinct from brain-resident microglia. Mice expressing pathogenic LRRK2 mutations G2019S or R1441C have increased numbers of infiltrating pro-inflammatory monocytes in acute response to α-synuclein fibrils. In primary cultured macrophages, LRRK2 kinase inhibition dampens α-synuclein fibril and microglia-stimulated chemotaxis. Conclusions Pathologic α-synuclein activates LRRK2 expression and kinase activity in monocytes and induces their recruitment to the brain. These results predict that LRRK2 kinase inhibition may attenuate damaging pro-inflammatory monocyte responses in the brain.https://doi.org/10.1186/s13024-021-00509-5SNCAPARK8Monocyte extravasationNeurodegeneration |
| spellingShingle | Enquan Xu Ravindra Boddu Hisham A. Abdelmotilib Arpine Sokratian Kaela Kelly Zhiyong Liu Nicole Bryant Sidhanth Chandra Samantha M. Carlisle Elliot J. Lefkowitz Ashley S. Harms Etty N. Benveniste Talene A. Yacoubian Laura A. Volpicelli-Daley David G. Standaert Andrew B. West Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain Molecular Neurodegeneration SNCA PARK8 Monocyte extravasation Neurodegeneration |
| title | Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain |
| title_full | Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain |
| title_fullStr | Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain |
| title_full_unstemmed | Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain |
| title_short | Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain |
| title_sort | pathological α synuclein recruits lrrk2 expressing pro inflammatory monocytes to the brain |
| topic | SNCA PARK8 Monocyte extravasation Neurodegeneration |
| url | https://doi.org/10.1186/s13024-021-00509-5 |
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