Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease
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 p...
Main Authors: | , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2021-01-01
|
Series: | Neurobiology of Disease |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996120304599 |
id |
doaj-a5bad6c2bad44d15846ecd9b79a9ef39 |
---|---|
record_format |
Article |
spelling |
doaj-a5bad6c2bad44d15846ecd9b79a9ef392021-03-22T08:42:50ZengElsevierNeurobiology of Disease1095-953X2021-01-01148105184Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human diseaseDavid J. Marmion0Angela A. Rutkowski1Diptaman Chatterjee2Benjamin M. Hiller3Milton H. Werner4Erwan Bezard5Deniz Kirik6Thomas McCown7Steven J. Gray8Jeffrey H. Kordower9Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA; Parkinson's Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, United StatesDepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USADepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USADepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USAInhibikase Therapeutics, Inc., Atlanta, GA, USAUniversity of Bordeaux, Neurodegenerative Diseases Institute, UMR 5293, F-33000 Bordeaux, France; CNRS, Neurodegenerative Diseases Institute, UMR 5293, F-33000 Bordeaux, FranceBrain Repair and Imaging in Neural Systems (B.R.A.I.N.S) Unit, Department of Experimental Medical Science, Lund University, Lund 221 00, SwedenGene Therapy Center, University of North Carolina, Chapel Hill, NC, USA; Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USADepartment of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, United StatesDepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA; Corresponding author at: Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USAMultiple 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.http://www.sciencedirect.com/science/article/pii/S0969996120304599Multiple system atrophyAlpha synucleinNonhuman primateModelsOligodendroglia |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
David J. Marmion Angela A. Rutkowski Diptaman Chatterjee Benjamin M. Hiller Milton H. Werner Erwan Bezard Deniz Kirik Thomas McCown Steven J. Gray Jeffrey H. Kordower |
spellingShingle |
David J. Marmion Angela A. Rutkowski Diptaman Chatterjee Benjamin M. Hiller Milton H. Werner Erwan Bezard Deniz Kirik Thomas McCown Steven J. Gray Jeffrey H. Kordower Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease Neurobiology of Disease Multiple system atrophy Alpha synuclein Nonhuman primate Models Oligodendroglia |
author_facet |
David J. Marmion Angela A. Rutkowski Diptaman Chatterjee Benjamin M. Hiller Milton H. Werner Erwan Bezard Deniz Kirik Thomas McCown Steven J. Gray Jeffrey H. Kordower |
author_sort |
David J. Marmion |
title |
Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease |
title_short |
Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease |
title_full |
Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease |
title_fullStr |
Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease |
title_full_unstemmed |
Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease |
title_sort |
viral-based rodent and nonhuman primate models of multiple system atrophy: fidelity to the human disease |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2021-01-01 |
description |
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. |
topic |
Multiple system atrophy Alpha synuclein Nonhuman primate Models Oligodendroglia |
url |
http://www.sciencedirect.com/science/article/pii/S0969996120304599 |
work_keys_str_mv |
AT davidjmarmion viralbasedrodentandnonhumanprimatemodelsofmultiplesystematrophyfidelitytothehumandisease AT angelaarutkowski viralbasedrodentandnonhumanprimatemodelsofmultiplesystematrophyfidelitytothehumandisease AT diptamanchatterjee viralbasedrodentandnonhumanprimatemodelsofmultiplesystematrophyfidelitytothehumandisease AT benjaminmhiller viralbasedrodentandnonhumanprimatemodelsofmultiplesystematrophyfidelitytothehumandisease AT miltonhwerner viralbasedrodentandnonhumanprimatemodelsofmultiplesystematrophyfidelitytothehumandisease AT erwanbezard viralbasedrodentandnonhumanprimatemodelsofmultiplesystematrophyfidelitytothehumandisease AT denizkirik viralbasedrodentandnonhumanprimatemodelsofmultiplesystematrophyfidelitytothehumandisease AT thomasmccown viralbasedrodentandnonhumanprimatemodelsofmultiplesystematrophyfidelitytothehumandisease AT stevenjgray viralbasedrodentandnonhumanprimatemodelsofmultiplesystematrophyfidelitytothehumandisease AT jeffreyhkordower viralbasedrodentandnonhumanprimatemodelsofmultiplesystematrophyfidelitytothehumandisease |
_version_ |
1724209297248747520 |