Multiple system atrophy: experimental models and reality

Multiple system atrophy (MSA) is a rapidly progressing fatal synucleinopathy of the aging population characterized by parkinsonism, dysautonomia, and in some cases ataxia. Unlike other synucleinopathies, in this disorder the synaptic protein, α-synuclein (α-syn), predominantly accumulates in oligodendroglial cells (and to some extent in neurons), leading to maturation defects of oligodendrocytes, demyelination, and neurodegeneration. The mechanisms through which α-syn deposits occur in oligodendrocytes and neurons in MSA are not completely clear. While some studies suggest that α-syn might transfer from neurons to glial cells, others propose that α-syn might be aberrantly overexpressed by oligodendroglial cells. A number of in vivo models have been developed, including transgenic mice overexpressing α-syn under oligodendroglial promoters (e.g.: MBP, PLP, and CNP). Other models have been recently developed either by injecting synthetic α-syn fibrils or brain homogenates from patients with MSA into wild-type mice or by using viral vectors expressing α-syn under the MBP promoter in rats and non-human primates. Each of these models reproduces some of the neuropathological and functional aspects of MSA; however, none of them fully replicate the spectrum of MSA. Understanding better the mechanisms of how α-syn accumulates in oligodendrocytes and neurons will help in developing better models that recapitulate various pathogenic aspects of MSA in combination with translatable biomarkers of early stages of the disease that are necessary to devise disease-modifying therapeutics for MSA.