Inhibition of copper transporter 1 prevents α-synuclein pathology and alleviates nigrostriatal degeneration in AAV-based mouse model of Parkinson's disease
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
Affiliations
De-Hai Gou
Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China
Ting-Ting Huang
Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China
Wen Li
Institute of Health Sciences, China Medical University, Shenyang, 110122, China; Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, 22184, Lund, Sweden
Xin-Di Gao
Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China
Caroline Haikal
Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, 22184, Lund, Sweden
Xin-He Wang
Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China
Dong-Yan Song
Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China
Xin Liang
Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, China; Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, China
Lin Zhu
Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, China; Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, China
Yong Tang
Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, China; Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, China
Chen Ding
Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China; Corresponding author.
Jia-Yi Li
Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China; Institute of Health Sciences, China Medical University, Shenyang, 110122, China; Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, 22184, Lund, Sweden; Corresponding author. Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China.
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.
