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

Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease.
Neurobiol Dis. 2020 Nov 19;:105184
Authors: Marmion DJ, Rutkowski AA, Chatterjee D, Hiller BM, Werner MH, Bezard E, Kirik D, McCown T, Gray SJ, Kordower JH
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...

Source: Neurobiology of Disease - November 19, 2020 Category: Neurology Authors: Marmion DJ, Rutkowski AA, Chatterjee D, Hiller BM, Werner MH, Bezard E, Kirik D, McCown T, Gray SJ, Kordower JH Tags: Neurobiol Dis Source Type: research