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 variants and
Parkinson's disease in one of the cohorts (P = 0.002). Despite a small upregulation in
MERTK mRNA expression in nigral microglia from
Parkinson's disease/Lewy body dementia patients compared to those from non-neurological control donors in a single-nuclei
RNA-sequencing dataset (P = 5.08 × 10-21), no significant upregulation in
MerTK protein expression was observed in human cortex and substantia nigra lysates from
Lewy body dementia patients compared to controls. Taken together, our findings define a novel role for
MerTK in mediating the uptake of
alpha-synuclein fibrils by human microglia, with possible involvement in limiting
alpha-synuclein spread in
synucleinopathies such as
Parkinson's disease. Upregulation of this pathway in
synucleinopathies could have therapeutic values in enhancing
alpha-synuclein fibril clearance in the brain.