Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease
Parkinson's disease (PD) is the second most common neurodegenerative disease. Pathologically, PD is characterized by the formation of Lewy bodies (LBs) in the brain, which mainly comprises phosphorylated and aggregated α-synuclein (α-syn). The aberrant aggregation of α-syn is believed to play a...
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doaj-518dcd18411f448cb806807153ffcb3f2021-03-22T08:42:57ZengElsevierNeurobiology of Disease1095-953X2021-01-01148105218Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's diseaseJiaolong Yang0Shilin Luo1Jichun Zhang2Ting Yu3Zhihui Fu4Yongfa Zheng5Ximing Xu6Chaoyang Liu7Mingxia Fan8Zhentao Zhang9Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaDepartment of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha 410011, ChinaDepartment of Physiology, School of Medicine, Jinan University, Guangzhou 510632, ChinaDepartment of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaDepartment of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaDepartment of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaDepartment of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaDepartment of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Research Center for Environment and Health, Zhongnan University of Economics and Law, Wuhan 430073, ChinaAnimal Experiment Center, Renmin Hospital of Wuhan University, Wuhan 430060, China; Corresponding authors.Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Corresponding authors.Parkinson's disease (PD) is the second most common neurodegenerative disease. Pathologically, PD is characterized by the formation of Lewy bodies (LBs) in the brain, which mainly comprises phosphorylated and aggregated α-synuclein (α-syn). The aberrant aggregation of α-syn is believed to play a key role in the pathogenesis of PD. While α-syn expression can be reduced by antisense oligonucleotides (ASOs), the challenge to deliver ASOs safely and effectively into the neurons remains unresolved. Here, we developed a safe and highly effective ASO delivery method by using exosomes. We first identified the ASO sequence that selectively reduced α-syn expression: ASO4. Exosome-mediated delivery of ASO4 (exo-ASO4) showed high cellular uptake and low toxicity in primary neuronal cultures. Exo-ASO4 also significantly attenuated α-syn aggregation induced by pre-formed α-syn fibrils in vitro. Exo-ASO4 intracerebroventricular injection into the brains of α-syn A53T mice, a transgenic model of PD, significantly decreased the expression of α-syn and attenuated its aggregation. Furthermore, exo-ASO4 ameliorated the degeneration of dopaminergic neurons in these mice. Finally, the α-syn A53T mice showed significantly improved locomotor functions after exo-ASO4 injection. Overall, this study demonstrates that exosome-mediated ASO4 delivery may be an effective treatment option for PD.http://www.sciencedirect.com/science/article/pii/S0969996120304939Parkinson's diseaseExosomesAntisense oligonucleotidesα-synucleinPhosphorylated α-synuclein |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jiaolong Yang Shilin Luo Jichun Zhang Ting Yu Zhihui Fu Yongfa Zheng Ximing Xu Chaoyang Liu Mingxia Fan Zhentao Zhang |
spellingShingle |
Jiaolong Yang Shilin Luo Jichun Zhang Ting Yu Zhihui Fu Yongfa Zheng Ximing Xu Chaoyang Liu Mingxia Fan Zhentao Zhang Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease Neurobiology of Disease Parkinson's disease Exosomes Antisense oligonucleotides α-synuclein Phosphorylated α-synuclein |
author_facet |
Jiaolong Yang Shilin Luo Jichun Zhang Ting Yu Zhihui Fu Yongfa Zheng Ximing Xu Chaoyang Liu Mingxia Fan Zhentao Zhang |
author_sort |
Jiaolong Yang |
title |
Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease |
title_short |
Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease |
title_full |
Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease |
title_fullStr |
Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease |
title_full_unstemmed |
Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease |
title_sort |
exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of parkinson's disease |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2021-01-01 |
description |
Parkinson's disease (PD) is the second most common neurodegenerative disease. Pathologically, PD is characterized by the formation of Lewy bodies (LBs) in the brain, which mainly comprises phosphorylated and aggregated α-synuclein (α-syn). The aberrant aggregation of α-syn is believed to play a key role in the pathogenesis of PD. While α-syn expression can be reduced by antisense oligonucleotides (ASOs), the challenge to deliver ASOs safely and effectively into the neurons remains unresolved. Here, we developed a safe and highly effective ASO delivery method by using exosomes. We first identified the ASO sequence that selectively reduced α-syn expression: ASO4. Exosome-mediated delivery of ASO4 (exo-ASO4) showed high cellular uptake and low toxicity in primary neuronal cultures. Exo-ASO4 also significantly attenuated α-syn aggregation induced by pre-formed α-syn fibrils in vitro. Exo-ASO4 intracerebroventricular injection into the brains of α-syn A53T mice, a transgenic model of PD, significantly decreased the expression of α-syn and attenuated its aggregation. Furthermore, exo-ASO4 ameliorated the degeneration of dopaminergic neurons in these mice. Finally, the α-syn A53T mice showed significantly improved locomotor functions after exo-ASO4 injection. Overall, this study demonstrates that exosome-mediated ASO4 delivery may be an effective treatment option for PD. |
topic |
Parkinson's disease Exosomes Antisense oligonucleotides α-synuclein Phosphorylated α-synuclein |
url |
http://www.sciencedirect.com/science/article/pii/S0969996120304939 |
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