MerTK is a mediator of alpha-synuclein fibril uptake by human microglia

作者：Marie‐France Dorion, Moein Yaqubi, Konstantin Senkevich, Nicholas W. Kieran, Adam MacDonald, Carol X-Q Chen, Wen Luo, Amber Wallis, Irina Shlaifer, Jeffery A. Hall, Roy Dudley, Ian A. Glass, Jo Anne Stratton, Edward A. Fon, Tim Bartels, Jack P. Antel, Ziv Gan‐Or, Thomas M. Durcan, Luke M. Healy · 发表于：Brain · 年份：2023 · DOI：10.1093/brain/awad298 · 被引用次数：40 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Phagocytosis and Immune Regulation、Nuclear Receptors and Signaling

Mer tyrosine kinase (MerTK) is a receptor tyrosine kinase that mediates non-inflammatory, homeostatic phagocytosis of diverse types of cellular debris. Highly expressed on the surface of microglial cells, MerTK is of importance in brain development, homeostasis, plasticity and disease. Yet, involvement of this receptor in the clearance of protein aggregates that accumulate with ageing and in neurodegenerative diseases has yet to be defined. The current study explored the function of MerTK in the microglial uptake of alpha-synuclein fibrils which play a causative role in the pathobiology of synucleinopathies. Using human primary and induced pluripotent stem cell-derived microglia, the MerTK-dependence of alpha-synuclein fibril internalization was investigated in vitro. Relevance of this pathway in synucleinopathies was assessed through burden analysis of MERTK variants and analysis of MerTK expression in patient-derived cells and tissues. Pharmacological inhibition of MerTK and siRNA-mediated MERTK knockdown both caused a decreased rate of alpha-synuclein fibril internalization by human microglia. Consistent with the non-inflammatory nature of MerTK-mediated phagocytosis, alpha-synuclein fibril internalization was not observed to induce secretion of pro-inflammatory cytokines such as IL-6 or TNF, and downmodulated IL-1β secretion from microglia. Burden analysis in two independent patient cohorts revealed a significant association between rare functionally deleterious MERTK var...