Monocyte-derived microglia with Dnmt3a mutation cause motor pathology in aging mice

Jung-Seok Kim, Sébastien Trzebanski, Sun-Hye Shin, Noa Chapal Ilani, Nathali Kaushansky, Marina Scheller, Aryeh Solomon, Zhaoyuan Liu, Oliver Aust, Sigalit Boura-Halfon, Lukas Amann, Marco Prinz, Florent Ginhoux, Roi Avraham, Carsten Müller-Tidow, Stefan Uderhardt, Ivan Milenkovic, Liran Shlush, Steffen Jung
bioRxiv (2023)


Microglia are established in embryogenesis forming a self-containing cellular compartment resisting seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦ) accumulate in the brain of aging mice with distinct topology, including the nigrostriatum and medulla, but not the frontal cortex. Parenchymal MoMΦ adopt bona fide microglia expression profiles. Unlike microglia, these monocyte-derived microglia (MoMg) are due to their hematopoietic origin targets of clonal hematopoiesis (CH). Using a chimeric transfer model, we show that hematopoietic expression of DNMT3AR822H, a prominent mutation in human CH, renders MoMg pathogenic promoting motor deficits resembling atypical Parkinsonian disorders. Collectively, these data establish in a mouse model that MoMg progressively seed the brains of aging healthy mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can contribute to brain pathology.