Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.04.077065v1?rss=1 Authors: 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. Abstract: Missense mutations in the LRRK2 gene that lead to LRRK2 kinase hyperactivity can cause Parkinson's disease (PD). The link between LRRK2 and a-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 a-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 a-synuclein. LRRK2 kinase inhibition blocks a-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-g 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. Copy rights belong to original authors. Visit the link for more info