Mechanism of neurodegeneration mediated by clonal inflammatory microglia

Author:

Vicario Rocio,Fragkogianni Stamatina,Pokrovskii Maria,Mayer Carina,Lopez-Rodrigo Estibaliz,Hu Yang,Ogishi MasatoORCID,Alberdi Araitz,Baako Ann,Ay Oyku,Plu IsabelleORCID,Sazdovitch Véronique,Heritier Sebastien,Cohen-Aubart Fleur,Shor Natalia,Miyara Makoto,Nguyen-Khac Florence,Viale Agnes,Idbaih Ahmed,Amoura Zahir,Rosenblum Marc K.,Zhang Haochen,Karnoub Elias-Ramzey,Sashittal Palash,Jakatdar Akhil,Iacobuzio-Donahue Christine A.ORCID,Abdel-Wahab Omar,Tabar Viviane,Socci Nicholas D.,Elemento Olivier,Diamond Eli L,Boisson Bertrand,Casanova Jean-Laurent,Seilhean Danielle,Haroche Julien,Donadieu JeanORCID,Geissmann Frederic

Abstract

SummaryLangerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and an increased risk of neurodegeneration. Surprisingly, we found pervasive PU.1+microglia mutant clones across the brain of LCH and ECD patients with and without neurological symptoms, associated with microgliosis, reactive astrocytosis, and neuronal loss. The disease predominated in the grey nuclei of the rhombencephalon, a topography attributable to a local proliferative advantage of mutant microglia. Presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1+clones (p= 0.0003). Genetic lineage tracing of PU.1+clones suggest a resident macrophage lineage or a bone marrow precursor origin depending on patients. Finally, a CSF1R-inhibitor depleted mutant microglia and limited neuronal loss in mice suggesting an alternative to MAPK inhibitors. These studies characterize a progressive neurodegenerative disease, caused by clonal proliferation of inflammatory microglia (CPIM), with a decade(s)-long preclinical stage of incipient disease that represent a therapeutic window for prevention of neuronal death.

Publisher

Cold Spring Harbor Laboratory

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3