Somatic mosaicism in microglia - a model for neurodegeneration in histiocytosis and implications for treatment

Abstract: Histiocytoses are rare and heterogenous clonal myeloid malignancies affecting different tissues. Somatic mutations conferring constitutive activation of the MAP Kinase pathway have been identified in these patients, with BRAFV600E present in up to 50-60% of the cases. Neurodegenerative disease is a rare but lethal complication seen in a proportion of patients with no effective therapeutic options to date. We have demonstrated in a murine model that mosaic BRAFV600E mutations in microglia, the tissue resident macrophages in the brain, lead to a neurodegenerative disease in mice resembling that seen in histiocytosis patients. Mutant microglia are over-activated, with microgliosis occurring preferentially in the white matter of the hindbrain and the spinal cord, with a unique role of the spinocerebellar tract in symptomatic mice. However, the BRAFVE clones can be found in high percentages in all brain areas, showing a heterogenous behavior of mutant microglia dependent on their microenvironment. We have previously reported that a BRAF inhibitor (PLX4720) deferred symptoms and progression when administered early prior to disease onset. We now tested a different therapeutic strategy, depletion of microglia using the CSF1R inhibitor (PLX5622) instead, or the combination of both drugs. Csf1r inhibition is depleting mutant microglia, however a selection and formation of resistance can occur over time through the loss of Csf1r expression. Both inhibitors alone can delay disease progression, however relapse of disease is occurring. The combination of both drugs shows an additive effect leading to a significant improvement in disease progression and survival

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2020

Classification and Topics

• Keyword: Microglia ; Mosaicism ; Nervendegeneration ; Histiozytose ; Somatische Mutation

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2021
• Creator: Meyer, Carina
• Contributor: Prinz, Marco ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Further information

• DOI: 10.6094/UNIFR/175767
• URN: urn:nbn:de:bsz:25-freidok-1757671
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:41 PM CET