Pathologic α-Synuclein Species Activate LRRK2 in Pro-Inflammatory Monocyte and Macrophage Responses

Xu, E.; Boddu, R.; Abdelmotilib, H. A.; Kelly, K.; Sokratian, A.; Harms, A. S.; Schonhoff, A. M.; Bryant, N.; Harmsen, I. E.; Schlossmacher, M.; Chandra, S.; Krendelshchikova, V.; Liu, Z.; West, A. B.

doi:10.1101/2020.05.04.077065

bioRxiv · 10.1101/2020.05.04.077065

Pathologic α-Synuclein Species Activate LRRK2 in Pro-Inflammatory Monocyte and Macrophage Responses

Xu, E.·Boddu, R.·Abdelmotilib, H. A.·Kelly, K.·Sokratian, A.·Harms, A. S.·Schonhoff, A. M.·Bryant, N.·Harmsen, I. E.·Schlossmacher, M.·Chandra, S.·Krendelshchikova, V.·Liu, Z.·West, A. B.

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Abstract

Missense mutations in the LRRK2 gene that lead to LRRK2 kinase hyperactivity can cause Parkinsons disease (PD). The link between LRRK2 and -synuclein aggregation in PD remains enigmatic. Numerous reports suggest critical LRRK2 functions in microglial responses. Herein, we find that LRRK2-positive immune cells in the brain represent CD68-positive pro-inflammatory, monocyte-derived macrophages, distinct from microglia. Rod -synuclein fibrils stimulate LRRK2 kinase activity in monocyte-derived macrophages, and LRRK2 mutations lead to enhanced recruitment of classical monocytes into the midbrain in response to -synuclein. LRRK2 kinase inhibition blocks -synuclein fibril induction of LRRK2 protein in both human and murine macrophages, with human cells demonstrating much higher LRRK2 levels and kinase activity than equivalent murine cells. Further, interferon-{gamma} strongly induces LRRK2 kinase activity in primary human macrophages in comparison to weak effects observed in murine cells. These results highlight peripheral immune responses in LRRK2-linked paradigms that further connect two central proteins in PD.

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Xu, E., Boddu, R., Abdelmotilib, H. A., Kelly, K., Sokratian, A., Harms, A. S., Schonhoff, A. M., Bryant, N., Harmsen, I. E., Schlossmacher, M., Chandra, S., Krendelshchikova, V., Liu, Z., West, A. B.. 2020-05-05. Pathologic α-Synuclein Species Activate LRRK2 in Pro-Inflammatory Monocyte and Macrophage Responses. https://doi.org/10.1101/2020.05.04.077065

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