Inhibition of copper transporter 1 prevents α-synuclein pathology and alleviates nigrostriatal degeneration in AAV-based mouse model of Parkinson's disease
| Autor: | Ting Ting Huang, Xin Di Gao, Xin Liang, Yong Tang, Chen Ding, Caroline Haikal, Dong Yan Song, Jia-Yi Li, De Hai Gou, Xin He Wang, Wen Li, Lin Zhu |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Pathology medicine.medical_specialty Parkinson's disease Synucleinopathies animal diseases Clinical Biochemistry chemistry.chemical_element Mice Transgenic Substantia nigra Biochemistry Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Neurodegeneration lcsh:QH301-705.5 Copper transporter 1 α-Synuclein lcsh:R5-920 Chemistry Organic Chemistry Dopaminergic Parkinson Disease medicine.disease Copper nervous system diseases Nigrostriatal system Disease Models Animal 030104 developmental biology lcsh:Biology (General) nervous system alpha-Synuclein lcsh:Medicine (General) 030217 neurology & neurosurgery Intracellular Research Paper |
| Zdroj: | Redox Biology Redox Biology, Vol 38, Iss, Pp 101795-(2021) |
| ISSN: | 2213-2317 |
| DOI: | 10.1016/j.redox.2020.101795 |
| Popis: | 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. Graphical abstract Image 1 Highlights • Ctr1 deficiency reduces α-synuclein aggregates in vitro. • Ctr1 deficiency inhibits the level of pathological α-synuclein in vivo. • Ctr1 deficiency prevents nigrostriatal neurodegeneration in vivo. • Ctr1 deficiency alleviates motor dysfunction caused by α-synuclein in vivo. |
| Databáze: | OpenAIRE |
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