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Viral-based rodent ...
Viral-based rodent and nonhuman primate models of multiple system atrophy : Fidelity to the human disease
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- Marmion, David J. (författare)
- Rush University Medical Center Chicago,Barrow Neurological Institute, Phoenix
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- Rutkowski, Angela A. (författare)
- Rush University Medical Center Chicago
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- Chatterjee, Diptaman (författare)
- Rush University Medical Center Chicago
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- Hiller, Benjamin M. (författare)
- Rush University Medical Center Chicago
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- Werner, Milton H. (författare)
- Inhibikase Therapeutics, Inc.
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- Bezard, Erwan (författare)
- University of Bordeaux
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- Kirik, Deniz (författare)
- Lund University,Lunds universitet,Brain Repair and Imaging in Neural Systems (BRAINS),Forskargrupper vid Lunds universitet,Lund University Research Groups
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- McCown, Thomas (författare)
- University of North Carolina
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- Gray, Steven J. (författare)
- University of Texas Southwestern Medical Center
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- Kordower, Jeffrey H. (författare)
- Rush University Medical Center Chicago
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(creator_code:org_t)
- Elsevier BV, 2021
- 2021
- Engelska.
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 148
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Nyckelord
- Alpha synuclein
- Models
- Multiple system atrophy
- Nonhuman primate
- Oligodendroglia
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Marmion, David J ...
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Rutkowski, Angel ...
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Chatterjee, Dipt ...
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Hiller, Benjamin ...
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Werner, Milton H ...
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Bezard, Erwan
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visa fler...
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Kirik, Deniz
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McCown, Thomas
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Gray, Steven J.
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Kordower, Jeffre ...
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Neurologi
- Artiklar i publikationen
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Neurobiology of ...
- Av lärosätet
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Lunds universitet