Viral-based rodent and nonhuman primate models of multiple system atrophy : Fidelity to the human disease
(2021) In Neurobiology of Disease 148.- 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... (More)
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 cynomolgus macaques. After six months, histological analysis showed that oligodendroglial overexpression of aSyn resulted in the formation of hallmark GCIs throughout the putamen, demyelination, a 44% reduction of striatal neurons and a 12% loss of nigral neurons. Furthermore, a robust inflammatory response similar to MSA was produced in Olig001-aSyn NHPs, including microglial activation, astrogliosis, and a robust infiltration of T cells into the CNS. Taken together, oligodendroglial-specific viral vector-mediated overexpression of aSyn in rats and nonhuman primates faithfully reproduces many of the pathological disease hallmarks found in MSA. Future studies utilizing these large animal models of MSA would prove extremely valuable as a pre-clinical platform to test novel therapeutics that are so desperately needed for MSA.
(Less)
- author
- Marmion, David J. ; Rutkowski, Angela A. ; Chatterjee, Diptaman ; Hiller, Benjamin M. ; Werner, Milton H. ; Bezard, Erwan ; Kirik, Deniz LU ; McCown, Thomas ; Gray, Steven J. and Kordower, Jeffrey H.
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Alpha synuclein, Models, Multiple system atrophy, Nonhuman primate, Oligodendroglia
- in
- Neurobiology of Disease
- volume
- 148
- article number
- 105184
- publisher
- Elsevier
- external identifiers
-
- pmid:33221532
- scopus:85096860474
- ISSN
- 0969-9961
- DOI
- 10.1016/j.nbd.2020.105184
- language
- English
- LU publication?
- yes
- id
- ace60070-ebca-4b29-994c-6362e91737fa
- date added to LUP
- 2020-12-09 13:36:15
- date last changed
- 2024-05-01 21:47:55
@article{ace60070-ebca-4b29-994c-6362e91737fa,
abstract = {{<p>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 cynomolgus macaques. After six months, histological analysis showed that oligodendroglial overexpression of aSyn resulted in the formation of hallmark GCIs throughout the putamen, demyelination, a 44% reduction of striatal neurons and a 12% loss of nigral neurons. Furthermore, a robust inflammatory response similar to MSA was produced in Olig001-aSyn NHPs, including microglial activation, astrogliosis, and a robust infiltration of T cells into the CNS. Taken together, oligodendroglial-specific viral vector-mediated overexpression of aSyn in rats and nonhuman primates faithfully reproduces many of the pathological disease hallmarks found in MSA. Future studies utilizing these large animal models of MSA would prove extremely valuable as a pre-clinical platform to test novel therapeutics that are so desperately needed for MSA.</p>}},
author = {{Marmion, David J. and Rutkowski, Angela A. and Chatterjee, Diptaman and Hiller, Benjamin M. and Werner, Milton H. and Bezard, Erwan and Kirik, Deniz and McCown, Thomas and Gray, Steven J. and Kordower, Jeffrey H.}},
issn = {{0969-9961}},
keywords = {{Alpha synuclein; Models; Multiple system atrophy; Nonhuman primate; Oligodendroglia}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{Neurobiology of Disease}},
title = {{Viral-based rodent and nonhuman primate models of multiple system atrophy : Fidelity to the human disease}},
url = {{http://dx.doi.org/10.1016/j.nbd.2020.105184}},
doi = {{10.1016/j.nbd.2020.105184}},
volume = {{148}},
year = {{2021}},
}