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Adenovirus-induced Reactive Astrogliosis Exacerbates the Pathology of Parkinson's Disease

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Title
Adenovirus-induced Reactive Astrogliosis Exacerbates the Pathology of Parkinson's Disease
Author(s)
Heeyoung An; Lee, Hyowon; Yang, Seulkee; Woojin Won; C. Justin Lee; Nam, Min-Ho
Publication Date
2021-06
Journal
EXPERIMENTAL NEUROBIOLOGY, v.30, no.3, pp.222 - 231
Publisher
KOREAN SOC BRAIN & NEURAL SCIENCE, KOREAN SOC NEURODEGENERATIVE DISEASE
Abstract
Parkinson's disease (PD) is the most prevalent neurodegenerative motor disorder. While PD has been attributed to dopaminergic neuronal death in substantia nigra pars compacta (SNpc), accumulating lines of evidence have suggested that reactive astrogliosis is critically involved in PD pathology. These pathological changes are associated with alpha-synuclein aggregation, which is more prone to be induced by an A53T mutation. Therefore, the overexpression of A53T-mutated alpha-synuclein (A53T-alpha-syn) has been utilized as a popular animal model of PD. However, this animal model only shows marginal-to-moderate extents of reactive astrogliosis and astrocytic alpha-synuclein accumulation, while these phenomena are prominent in human PD brains. Here we show that Adeno-GFAP-GFP virus injection into SNpc causes severe reactive astrogliosis and exacerbates the A53T alpha-syn-mediated PD pathology. In particular, we demonstrate that AAV-CMV-A53T-alpha-syn injection, when combined with Adeno-GFAP-GFP, causes more significant loss of dopaminergic neuronal tyrosine hydroxylase level and gain of astrocytic GFAP and GABA levels. Moreover, the combination of AAV-CMV-A53T-alpha-syn and Adeno-GFAP-GFP causes an extensive astrocytic alpha-syn expression, just as in human PD brains. These results are in marked contrast to previous reports that AAV-CMV-A53T-alpha-syn alone causes alpha-syn expression mostly in neurons but rarely in astrocytes. Furthermore, the combination causes a severe PD-like motor dysfunction as assessed by rotarod and cylinder tests within three weeks from the virus injection, whereas Adeno-GFAP-GFP alone or AAV-CMV-A53T-alpha-syn alone does not. Our findings implicate that inducing reactive astrogliosis exacerbates PD-like pathologies and propose the virus combination as an advanced strategy for developing a new animal model of PD.
URI
https://pr.ibs.re.kr/handle/8788114/10063
DOI
10.5607/en21013
ISSN
1226-2560
Appears in Collections:
Center for Cognition and Sociality(인지 및 사회성 연구단) > 1. Journal Papers (저널논문)
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