LRRK2 Shapes Myeloid-T Cell Responses in Idiopathic Parkinson’s Disease.

Abstract

Parkinson’s disease (PD) is partially characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN), often accompanied by the accumulation of aggregated α-synuclein in neurons and the local activation of myeloid cells. Recent genetic and transcriptomic studies have suggested a significant role for innate immune cells in disease risk and progression. Monocytes exhibit inflammatory responses in α-synuclein-associated disease, infiltrate the brain parenchyma, and contain uniquely high expression of the PD-linked enzyme, leucine-rich repeat kinase 2 (LRRK2), indicating a potentially crucial contribution of monocytes to disease pathology. However, whether LRRK2 promotes neurodegeneration through brain-resident or peripheral immune cells remains unclear. Here, we integrate human single-nucleus transcriptomic datasets with murine bone marrow chimeras to interrogate the compartment-specific contributions. Single-nucleus RNA sequencing identifies robust LRRK2 upregulation in non-canonical myeloid cell subsets specifically within PD SN. LRRK2-expressing myeloid cells bear markers of peripheral origins, with upregulated antigen presentation, downregulated phagocytosis, and correlations to T cell burdens. In murine bone marrow chimeras, selective depletion of LRRK2 from hematopoietic cells attenuated α-synuclein-induced dopaminergic neurodegeneration, and responses from myeloid cells and T cells. Our findings detail a non-cell-autonomous, evolutionarily conserved role for peripheral LRRK2 in orchestrating neuroinflammation and neuronal loss, supporting therapeutic strategies that target peripheral LRRK2 in PD and related synucleinopathies.