{"authors":[{"name":"C. Matthias Wilk","orcid":"0000-0001-5429-7143","role":"Author"},{"name":"Flurin Cathomas","orcid":"0000-0002-8274-1317","role":"Author"},{"name":"Orsolya Török","orcid":"0000-0001-8317-066X","role":"Author"},{"name":"Jessica Le Berichel","orcid":"","role":"Author"},{"name":"Matthew D. Park","orcid":"","role":"Author"},{"name":"George R. Heaton","orcid":"","role":"Author"},{"name":"Pauline Hamon","orcid":"0000-0002-6776-1635","role":"Author"},{"name":"Leanna Troncoso","orcid":"0000-0003-2529-9267","role":"Author"},{"name":"Brooks P. Scull","orcid":"","role":"Author"},{"name":"Diana Dangoor","orcid":"","role":"Author"},{"name":"Aymeric Silvin","orcid":"","role":"Author"},{"name":"Ryan Fleischmann","orcid":"","role":"Author"},{"name":"Meriem Belabed","orcid":"0000-0002-3210-1581","role":"Author"},{"name":"Howard Lin","orcid":"","role":"Author"},{"name":"Elias Merad Taouli","orcid":"","role":"Author"},{"name":"Steffen Boettcher","orcid":"0000-0001-9937-0957","role":"Author"},{"name":"Markus G. Manz","orcid":"0000-0002-4676-7931","role":"Author"},{"name":"Julia K. Kofler","orcid":"","role":"Author"},{"name":"Zhenyu Yue","orcid":"0000-0001-8730-8515","role":"Author"},{"name":"Sergio A. Lira","orcid":"","role":"Author"},{"name":"Florent Ginhoux","orcid":"0000-0002-2857-7755","role":"Author"},{"name":"John F. Crary","orcid":"","role":"Author"},{"name":"Kenneth L. McClain","orcid":"0000-0003-0725-6263","role":"Author"},{"name":"Jennifer L. Picarsic","orcid":"0000-0002-3718-6422","role":"Author"},{"name":"Scott J. Russo","orcid":"","role":"Author"},{"name":"Carl E. Allen","orcid":"0000-0002-6625-739X","role":"Author"},{"name":"Miriam Merad","orcid":"0000-0002-4481-7827","role":"Author"}],"components":[{"id":"root","name":"root","payload":{"cid":"bafybeidzjdwrjonitghb6sc7phg75zsfixodzlpak6yrq25i4bwckhilxq","path":"root"},"type":"data-bucket"},{"id":"1a73f0a2-4dd6-438d-86be-90f8300cb6c0","name":"2023.10.10.561744v1.full.pdf","payload":{"externalUrl":"https://www.biorxiv.org/content/10.1101/2023.10.10.561744v1.full.pdf","path":"root/preprint.pdf","title":"Preprint","url":"bafybeia4ohntyxcuxhc7oyet5g357d4bl5oppq6lulb5um3ugi7sgmca2i"},"starred":true,"subtype":"preprint","type":"pdf"},{"id":"b2f04f36-7d9a-4d1b-b115-6d3d542e9600","name":"","payload":{"externalUrl":"https://www.biorxiv.org/content/10.1101/2023.10.10.561744v1.full.pdf","path":"root/","url":"bafybeiffj43wsynzmtyxp3fzxk463g2rymyd5doylcvhm36okmepojcyb4"},"starred":false,"subtype":"research-article","type":"pdf"},{"id":"b5d5320f-5c74-4146-ba04-14b4099f3bac","name":"New Folder","type":{".jpg":"data"},"payload":{"cid":"draft","path":"root/New Folder"}},{"id":"22e4a8cd-4af9-41cc-b5fa-8302e65208d0","name":"Circulating senescent myeloid cells.jpg","type":"unknown","starred":false,"payload":{"path":"root/New Folder/Circulating senescent myeloid cells.jpg","cid":"pending"}}],"defaultLicense":"CC BY","description":"Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing MAPK activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some patients with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we show that LCH-ND is caused by myeloid cells that are clonal with peripheral LCH cells. We discovered that circulating BRAFV600E+ myeloid cells cause the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiate into senescent, inflammatory CD11a+ macrophages that accumulate in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent novel and targetable mechanisms of ND.","researchFields":[],"title":"Circulating senescent myeloid cells drive blood brain barrier breakdown and neurodegeneration","version":"desci-nodes-0.2.0","coverImage":"bafybeibo224flwvdq7xos5mvb3iu3solhdcbyubhwjlqse5up62l35jpuu","dpid":{"prefix":"beta","id":"195"}}