| First Author | Xu E | Year | 2022 |
| Journal | Mol Neurodegener | Volume | 17 |
| Issue | 1 | Pages | 7 |
| PubMed ID | 35012605 | Mgi Jnum | J:393593 |
| Mgi Id | MGI:6853842 | Doi | 10.1186/s13024-021-00509-5 |
| Citation | Xu E, et al. (2022) Pathological alpha-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain. Mol Neurodegener 17(1):7 |
| abstractText | BACKGROUND: Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson's disease (PD). Aggregated alpha-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 alpha-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 alpha-synuclein fibrils. LRRK2 expression and LRRK2-dependent Rab10 phosphorylation were measured with monoclonal antibodies, and myeloid cell responses to alpha-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 alpha-synuclein fibrils and microglia in Boyden chambers. RESULTS: alpha-synuclein fibrils robustly stimulate LRRK2 and Rab10 phosphorylation in human and mouse macrophages and dendritic-like cells. In these cells, alpha-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 alpha-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 alpha-synuclein fibrils. In primary cultured macrophages, LRRK2 kinase inhibition dampens alpha-synuclein fibril and microglia-stimulated chemotaxis. CONCLUSIONS: Pathologic alpha-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. |
