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

Kim, J.-S.; Trzebanski, S.; Shin, S.-H.; Ilani, N. C.; Kaushansky, N.; Scheller, M.; Solomon, A.; Liu, Z.; Aust, O.; Boura-Halfon, S.; Amann, L.; Prinz, M.; Ginhoux, F.; Avraham, R.; Mueller-Tidow, C.; Uderhardt, S.; Milenkovic, I.; Shlush, L.; Jung, S.

doi:10.1101/2023.11.16.567402

bioRxiv · 10.1101/2023.11.16.567402

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

Kim, J.-S.·Trzebanski, S.·Shin, S.-H.·Ilani, N. C.·Kaushansky, N.·Scheller, M.·Solomon, A.·Liu, Z.·Aust, O.·Boura-Halfon, S.·Amann, L.·Prinz, M.·Ginhoux, F.·Avraham, R.·Mueller-Tidow, C.·Uderhardt, S.·Milenkovic, I.·Shlush, L.·Jung, S.

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Abstract

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 (MoM{Phi}) accumulate in the brain of aging mice with distinct topology, including the nigrostriatum and medulla, but not the frontal cortex. Parenchymal MoM{Phi} 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.

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Kim, J.-S., Trzebanski, S., Shin, S.-H., Ilani, N. C., Kaushansky, N., Scheller, M., Solomon, A., Liu, Z., Aust, O., Boura-Halfon, S., Amann, L., Prinz, M., Ginhoux, F., Avraham, R., Mueller-Tidow, C., Uderhardt, S., Milenkovic, I., Shlush, L., Jung, S.. 2023-11-17. Monocyte-derived microglia with Dnmt3a mutation cause motor pathology in aging mice. https://doi.org/10.1101/2023.11.16.567402

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