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Inhibition of coppe...
Inhibition of copper transporter 1 prevents α-synuclein pathology and alleviates nigrostriatal degeneration in AAV-based mouse model of Parkinson's disease
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- Gou, De Hai (author)
- Northeastern University
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- Huang, Ting Ting (author)
- Northeastern University
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- Li, Wen (author)
- Lund University,Lunds universitet,Neural plasticitet och reparation,Forskargrupper vid Lunds universitet,Neural Plasticity and Repair,Lund University Research Groups,China Medical University, Shenyang
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- Gao, Xin Di (author)
- Northeastern University
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- Haikal, Caroline (author)
- Lund University,Lunds universitet,Neural plasticitet och reparation,Forskargrupper vid Lunds universitet,Neural Plasticity and Repair,Lund University Research Groups
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- Wang, Xin He (author)
- Northeastern University
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- Song, Dong Yan (author)
- Northeastern University
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- Liang, Xin (author)
- Chongqing Medical University
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- Zhu, Lin (author)
- Chongqing Medical University
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- Tang, Yong (author)
- Chongqing Medical University
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- Ding, Chen (author)
- Northeastern University
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- Li, Jia Yi (author)
- Lund University,Lunds universitet,Neural plasticitet och reparation,Forskargrupper vid Lunds universitet,Neural Plasticity and Repair,Lund University Research Groups,Northeastern University,China Medical University, Shenyang
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(creator_code:org_t)
- Elsevier BV, 2021
- 2021
- English.
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In: Redox Biology. - : Elsevier BV. - 2213-2317. ; 38
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https://doi.org/10.1...
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Abstract
Subject headings
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- The formation of α-synuclein aggregates is a major pathological hallmark of Parkinson's disease. Copper promotes α-synuclein aggregation and toxicity in vitro. The level of copper and copper transporter 1, which is the only known high-affinity copper importer in the brain, decreases in the substantia nigra of Parkinson's disease patients. However, the relationship between copper, copper transporter 1 and α-synuclein pathology remains elusive. Here, we aim to decipher the molecular mechanisms of copper and copper transporter 1 underlying Parkinson's disease pathology. We employed yeast and mammalian cell models expressing human α-synuclein, where exogenous copper accelerated intracellular α-synuclein inclusions and silencing copper transporter 1 reduced α-synuclein aggregates in vitro, suggesting that copper transporter 1 might inhibit α-synuclein pathology. To study our hypothesis in vivo, we generated a new transgenic mouse model with copper transporter 1 conditional knocked-out specifically in dopaminergic neuron. Meanwhile, we unilaterally injected adeno-associated viral human-α-synuclein into the substantia nigra of these mice. Importantly, we found that copper transporter 1 deficiency significantly reduced S129-phosphorylation of α-synuclein, prevented dopaminergic neuronal loss, and alleviated motor dysfunction caused by α-synuclein overexpression in vivo. Overall, our data indicated that inhibition of copper transporter 1 alleviated α-synuclein mediated pathologies and provided a novel therapeutic strategy for Parkinson's disease and other synucleinopathies.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- Copper transporter 1
- Neurodegeneration
- Nigrostriatal system
- Parkinson's disease
- α-Synuclein
Publication and Content Type
- art (subject category)
- ref (subject category)
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To the university's database
- By the author/editor
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Gou, De Hai
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Huang, Ting Ting
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Li, Wen
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Gao, Xin Di
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Haikal, Caroline
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Wang, Xin He
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show more...
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Song, Dong Yan
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Liang, Xin
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Zhu, Lin
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Tang, Yong
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Ding, Chen
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Li, Jia Yi
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Redox Biology
- By the university
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Lund University