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Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy : studies in rodents and nonhuman primates

Mandel, Ronald J; Marmion, David J; Kirik, Deniz LU ; Chu, Yaping; Heindel, Clifford; McCown, Thomas; Gray, Steven J and Kordower, Jeffrey H (2017) In Acta neuropathologica communications 5(1). p.47-47
Abstract

Multiple system atrophy (MSA) is a horrible and unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein (α-syn) accumulates preferentially in oligodendroglia rather than neurons. Glial cytoplasmic inclusions (GCIs) of α-syn are thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. To date, only a murine model using one of three promoters exist to study this disease. We sought to develop novel rat and nonhuman primate (NHP) models of MSA by overexpressing α-syn in oligodendroglia using a novel oligotrophic adeno-associated virus (AAV) vector, Olig001. To establish... (More)

Multiple system atrophy (MSA) is a horrible and unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein (α-syn) accumulates preferentially in oligodendroglia rather than neurons. Glial cytoplasmic inclusions (GCIs) of α-syn are thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. To date, only a murine model using one of three promoters exist to study this disease. We sought to develop novel rat and nonhuman primate (NHP) models of MSA by overexpressing α-syn in oligodendroglia using a novel oligotrophic adeno-associated virus (AAV) vector, Olig001. To establish tropism, rats received intrastriatal injections of Olig001 expressing GFP. Histological analysis showed widespread expression of GFP throughout the striatum and corpus callosum with >95% of GFP+ cells co-localizing with oligodendroglia and little to no expression in neurons or astrocytes. We next tested the efficacy of this vector in rhesus macaques with intrastriatal injections of Olig001 expressing GFP. As in rats, we observed a large number of GFP+ cells in gray matter and white matter tracts of the striatum and the corpus callosum, with 90-94% of GFP+ cells co-localizing with an oligodendroglial marker. To evaluate the potential of our vector to elicit MSA-like pathology in NHPs, we injected rhesus macaques intrastriatally with Olig001 expressing the α-syn transgene. Histological analysis 3-months after injection demonstrated widespread α-syn expression throughout the striatum as determined by LB509 and phosphorylated serine-129 α-syn immunoreactivity, all of which displayed as tropism similar to that seen with GFP. As in MSA, Olig001-α-syn GCIs in our model were resistant to proteinase K digestion and caused microglial activation. Critically, demyelination was observed in the white matter tracts of the corpus callosum and striatum of Olig001-α-syn but not Olig001-GFP injected animals, similar to the human disease. These data support the concept that this vector can provide novel rodent and nonhuman primate models of MSA.

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keywords
Animals, Astrocytes/metabolism, Brain/metabolism, Dependovirus/genetics, Disease Models, Animal, Endopeptidase K/metabolism, Female, Genetic Vectors, Green Fluorescent Proteins/genetics, HEK293 Cells, Humans, Macaca mulatta, Male, Microglia/metabolism, Multiple System Atrophy/metabolism, Neurons/metabolism, Oligodendroglia/metabolism, Rats, Sprague-Dawley, alpha-Synuclein/genetics
in
Acta neuropathologica communications
volume
5
issue
1
pages
47 - 47
publisher
BioMed Central
external identifiers
  • scopus:85033802675
ISSN
2051-5960
DOI
10.1186/s40478-017-0451-7
language
English
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yes
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f7b0f3b9-74c4-402f-8447-eb0e799d1124
date added to LUP
2019-06-18 14:42:44
date last changed
2019-08-14 04:39:58
@article{f7b0f3b9-74c4-402f-8447-eb0e799d1124,
  abstract     = {<p>Multiple system atrophy (MSA) is a horrible and unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein (α-syn) accumulates preferentially in oligodendroglia rather than neurons. Glial cytoplasmic inclusions (GCIs) of α-syn are thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. To date, only a murine model using one of three promoters exist to study this disease. We sought to develop novel rat and nonhuman primate (NHP) models of MSA by overexpressing α-syn in oligodendroglia using a novel oligotrophic adeno-associated virus (AAV) vector, Olig001. To establish tropism, rats received intrastriatal injections of Olig001 expressing GFP. Histological analysis showed widespread expression of GFP throughout the striatum and corpus callosum with &gt;95% of GFP+ cells co-localizing with oligodendroglia and little to no expression in neurons or astrocytes. We next tested the efficacy of this vector in rhesus macaques with intrastriatal injections of Olig001 expressing GFP. As in rats, we observed a large number of GFP+ cells in gray matter and white matter tracts of the striatum and the corpus callosum, with 90-94% of GFP+ cells co-localizing with an oligodendroglial marker. To evaluate the potential of our vector to elicit MSA-like pathology in NHPs, we injected rhesus macaques intrastriatally with Olig001 expressing the α-syn transgene. Histological analysis 3-months after injection demonstrated widespread α-syn expression throughout the striatum as determined by LB509 and phosphorylated serine-129 α-syn immunoreactivity, all of which displayed as tropism similar to that seen with GFP. As in MSA, Olig001-α-syn GCIs in our model were resistant to proteinase K digestion and caused microglial activation. Critically, demyelination was observed in the white matter tracts of the corpus callosum and striatum of Olig001-α-syn but not Olig001-GFP injected animals, similar to the human disease. These data support the concept that this vector can provide novel rodent and nonhuman primate models of MSA.</p>},
  author       = {Mandel, Ronald J and Marmion, David J and Kirik, Deniz and Chu, Yaping and Heindel, Clifford and McCown, Thomas and Gray, Steven J and Kordower, Jeffrey H},
  issn         = {2051-5960},
  keyword      = {Animals,Astrocytes/metabolism,Brain/metabolism,Dependovirus/genetics,Disease Models, Animal,Endopeptidase K/metabolism,Female,Genetic Vectors,Green Fluorescent Proteins/genetics,HEK293 Cells,Humans,Macaca mulatta,Male,Microglia/metabolism,Multiple System Atrophy/metabolism,Neurons/metabolism,Oligodendroglia/metabolism,Rats, Sprague-Dawley,alpha-Synuclein/genetics},
  language     = {eng},
  month        = {06},
  number       = {1},
  pages        = {47--47},
  publisher    = {BioMed Central},
  series       = {Acta neuropathologica communications},
  title        = {Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy : studies in rodents and nonhuman primates},
  url          = {http://dx.doi.org/10.1186/s40478-017-0451-7},
  volume       = {5},
  year         = {2017},
}