INTRODUCTION: Multiple System Atrophy (MSA) is a rare, sporadic, age-related synucleinopathy characterized by Parkinson-like motor symptoms and ataxia. There is no therapy for MSA other than symptomatic treatment. MSA is characterized pathologically by glial cytoplasmic inclusions (GCI) of α-synuclein (αSyn) occurring in oligodendrocytes leading to loss of myelination in the brain. METHODS: We recently utilized a peptide-mediated delivery method to systemically transport an anti-sense oligonucleotide (ASO) targeted to αSyn in a mouse model of MSA. We hypothesized that systemic delivery of αSyn ASO by peptide mediated delivery to a mouse model of MSA would reduce the αSyn accumulation in oligodendrocytes and reduce the overt pathology associated with MSA. RESULTS: Following monthly treatments of the αSyn ASO, we found increased myelination in the corpus callosum, cerebellum and brainstem. We also observed increased numbers of oligodendrocytes and reduced gliosis; however, we did not detect changes in overall αSyn in the areas of the brain we examined. Upon further analysis, we determined the peptide-mediated delivery of αSyn ASO was not taken up by oligodendrocytes. CONCLUSION: Thus, we have successfully alleviated some of the pathology associated with MSA in a mouse model; however, without direct delivery to oligodendrocytes, other approaches may need to supplement this therapy.