CSF1R-Mediated Myeloid Cell Depletion Prolongs Lifespan But Aggravates Distinct Motor Symptoms in a Model of Multiple System Atrophy

• DOI: 10.1523/jneurosci.0417-22.2022
• Publication Date: 2022-09-06T17:50:51Z
• Authors: Kristina Battis; Jazmin B. Florio; Michael Mante; Addison Lana; Isabel Naumann; Carina Gauer; Vera Lambrecht; Simon Julian Müller; Isidoro Cobo; Bethany Fixsen; Ha Yeon Kim; Eliezer Masliah; Christopher K. Glass; Johannes C. M. Sc...; Robert A. Rissman; Jürgen Winkler; Alana Hoffmann
• Keywords: IRF8

As the CNS-resident macrophages and member of myeloid lineage, microglia fulfill manifold functions important for brain development homeostasis. In context neurodegenerative diseases, they have been implicated in degenerative regenerative processes. The discovery distinct activation patterns, including increased phagocytosis, indicated a damaging role cells multiple system atrophy (MSA), devastating, rapidly progressing atypical parkinsonian disorder. Here, we analyzed gene expression profile mouse model MSA (<i>MBP29-h</i>α<i>-syn</i>) identified disease-associated upregulation colony-stimulating factor 1 (<i>Csf1</i>). Thus, hypothesized that CSF1 receptor-mediated depletion using PLX5622 modifies disease progression neuropathological phenotype this model. Intriguingly, sex-balanced analysis cell <i>MBP29-h</i>α<i>-syn</i> mice revealed two-faced outcome comprising an improved survival rate accompanied by delayed onset neurological symptoms contrast to severely impaired motor functions. Furthermore, reversed profiles related but reduced associated with transsynaptic signaling signal release. While transcriptional changes were reduction dopaminergic neurons SNpc, striatal neuritic density was upon mice. Together, our findings provide insight into complex, emphasizing importance carefully balance beneficial adverse effects CSF1R inhibition different models disorders before its clinical translation. <b>SIGNIFICANCE STATEMENT</b> Myeloid as detrimental pathogenesis atrophy. However, long-term CSF1R-dependent these demonstrates effect involving inflammation which contrasted functions, synaptic signaling, neuronal circuitries. study unraveled complex atrophy, indicates beyond previously described disease-associated, destructive emphasized need further investigation individually fine-tune immunologic processes diseases.