Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease.

Neurobiology of Disease
David J MarmionJeffrey H Kordower

Abstract

Multiple system atrophy (MSA) is a rare and extremely debilitating progressive neurodegenerative disease characterized by variable combinations of parkinsonism, cerebellar ataxia, dysautonomia, and pyramidal dysfunction. MSA is a unique synucleinopathy, in which alpha synuclein-rich aggregates are present in the cytoplasm of oligodendroglia. The precise origin of the alpha synuclein (aSyn) found in the glial cytoplasmic inclusions (GCIs) as well the mechanisms of neurodegeneration in MSA remain unclear. Despite this fact, cell and animal models of MSA rely on oligodendroglial overexpression of aSyn. In the present study, we utilized a novel oligotrophic AAV, Olig001, to overexpress aSyn specifically in striatal oligodendrocytes of rats and nonhuman primates in an effort to further characterize our novel viral vector-mediated MSA animal models. Using two cohorts of animals with 10-fold differences in Olig001 vector titers, we show a dose-dependent formation of MSA-like pathology in rats. High titer of Olig001-aSyn in these animals were required to produce the formation of pS129+ and proteinase K resistant aSyn-rich GCIs, demyelination, and neurodegeneration. Using this knowledge, we injected high titer Olig001 in the putamen of ...Continue Reading

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Citations

Apr 4, 2021·Biomedicines·Margaux TeilBenjamin Dehay
Jul 27, 2021·Frontiers in Pharmacology·Maria I Avrutsky, Carol M Troy
Oct 7, 2021·Journal of Neural Transmission·David J MarmionJeffrey H Kordower
Nov 25, 2021·Movement Disorders : Official Journal of the Movement Disorder Society·Milton H Werner, C Warren Olanow

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