TY - JOUR
T1 - Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy
T2 - studies in rodents and nonhuman primates
AU - Mandel, Ronald J.
AU - Marmion, David J.
AU - Kirik, Deniz
AU - Chu, Yaping
AU - Heindel, Clifford
AU - McCown, Thomas
AU - Gray, Steven J.
AU - Kordower, Jeffrey H.
N1 - Funding Information:
We acknowledge UNC Vector Core (directed by Jude Samulski) for the production of some of the AAV vectors used in these studies, Benjamin M. Hiller and Scott J. Muller for their support in the primate surgeries and care of the primates over the course of the study. Indirect administrative support for SJG was provided by Research to Prevent Blindness to the UNC-CH Department of Ophthalmology. Funding from the Michael J. Fox Foundation was used in the original generation of the Olig001 capsid. JHK received funding from a Center Grant from the Parkinson’s Disease Foundation supported this project.
PY - 2017/6/16
Y1 - 2017/6/16
N2 - 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.
AB - 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.
KW - Adeno-associated virus
KW - Alpha synuclein
KW - Multiple system atrophy
KW - Nonhuman primate
UR - http://www.scopus.com/inward/record.url?scp=85033802675&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85033802675&partnerID=8YFLogxK
U2 - 10.1186/s40478-017-0451-7
DO - 10.1186/s40478-017-0451-7
M3 - Article
C2 - 28619074
AN - SCOPUS:85033802675
SN - 2051-5960
VL - 5
SP - 47
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
IS - 1
ER -