The accumulation of aggregated α-synuclein in susceptible neurons in the brain, together with robust activation of nearby myeloid cells, are pathological hallmarks of Parkinson's disease (PD). While microglia represent the dominant type of myeloid cell in the brain, recent genetic and whole-transcriptomic studies have implicated another type of myeloid cell, bone-marrow derived monocytes, in disease risk and progression. Monocytes in circulation harbor high concentrations of the PD-linked enzyme leucine-rich repeat kinase 2 (LRRK2) and respond to both intracellular and extracellular aggregated α-synuclein with a variety of strong pro-inflammatory responses. This review highlights recent findings from studies that functionally characterize monocytes in PD patients, monocytes that infiltrate into cerebrospinal fluid, and emerging analyses of whole myeloid cell populations in the PD-affected brain that include monocyte populations. Central controversies discussed include the relative contribution of monocytes acting in the periphery from those that might engraft in the brain to modify disease risk and progression. We conclude that further investigation into monocyte pathways and responses in PD, especially the discovery of additional markers, transcriptomic signatures, and functional classifications, that better distinguish monocyte lineages and responses in the brain from other types of myeloid cells may reveal points for therapeutic intervention, as well as a better understanding of ongoing inflammation associated with PD.
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Cover Image
Cover Image
The cover of this edition of Biochemical Society Transactions features a super-resolution image of mouse heart mitochondria. Shammas, Huang and Narendra discuss the present understanding of neurodegeneration and myopathy caused by mutations in the mitochondrial proteins CHCHD2 and CHCHD10, and putting forth potential therapeutic strategies to combat these diseases in ‘CHCHD2 and CHCHD10-related neurodegeneration: molecular pathogenesis and the path to precision therapy’ on pp 797-809.
The interplay between monocytes, α-synuclein and LRRK2 in Parkinson's disease
Samuel Strader, Andrew B. West; The interplay between monocytes, α-synuclein and LRRK2 in Parkinson's disease. Biochem Soc Trans 26 April 2023; 51 (2): 747–758. doi: https://doi.org/10.1042/BST20201091
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