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  • Inhibition of copper transporter 1 prevents α-synuclein pathology and alleviates nigrostriatal degeneration in AAV-based mouse model of Parkinson's disease.

Inhibition of copper transporter 1 prevents α-synuclein pathology and alleviates nigrostriatal degeneration in AAV-based mouse model of Parkinson's disease.

Redox biology (2020-11-25)
De-Hai Gou, Ting-Ting Huang, Wen Li, Xin-Di Gao, Caroline Haikal, Xin-He Wang, Dong-Yan Song, Xin Liang, Lin Zhu, Yong Tang, Chen Ding, Jia-Yi Li
ABSTRACT

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.