Sex-Dependent Effects of CSF1R-Mediated Myeloid Cell Depletion in a Mouse Model of Multiple System Atrophy

Sex-dependent differences in neurodegenerative disorders are becoming increasingly relevant in diagnosis and development of therapeutic targets. Although multiple system atrophy (MSA), a devastating and rapidly progressing atypical parkinsonian disorder, is distributed equally among sexes, sex-specific differences have been reported regarding autonomic dysfunctions, severity of motor symptoms, and survival rate, suggesting a need for sex-specific treatment approaches. Neuroinflammation is a prominent hallmark in MSA pathology. Distinct activation patterns and increased phagocytosis of central nervous system (CNS) myeloid cells were observed, indicating a damaging role in this disease. In our previous study, we showed that colony-stimulating factor 1 receptor (CSF1R)-mediated depletion of myeloid cells in a mouse model of MSA led to a two-faced outcome, comprised of a prolonged survival and delayed onset of neurological dystonia-like symptoms, but also an aggravated motor phenotype and loss of dopaminergic neurons. Here, we re-analyzed our previous findings to study sex-specific effects in MSA in the presence and absence of CNS myeloid cells. Intriguingly, myeloid cell depletion was initially more effective in male animals. Although no sex-specific effects were detected in motor behavior, the occurrence of dystonia-like neurological symptoms was reduced, and neuronal loss was alleviated in male animals. Together, our findings provide insight into sex-specific differences of CSF1R-mediated myeloid cell depletion in MSA, emphasizing the need to study sex-specific treatment strategies in neurodegenerative disorders.