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

ABSTRACT

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.