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

The formation of alpha-synuclein aggregates is a major pathological hallmark of Parkinson's disease. Copper promotes alpha-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 alpha-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 alpha-synuclein, where exogenous copper accelerated intracellular alpha-synuclein inclusions and silencing copper transporter 1 reduced alpha-synuclein aggregates in vitro, suggesting that copper transporter 1 might inhibit alpha-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-alpha-synuclein into the substantia nigra of these mice. Importantly, we found that copper transporter 1 deficiency significantly reduced S129-phosphorylation of alpha-synuclein, prevented dopaminergic neuronal loss, and alleviated motor dysfunction caused by alpha-synuclein overexpression in vivo. Overall, our data indicated that inhibition of copper transporter 1 alleviated alpha-synuclein mediated pathologies and provided a novel therapeutic strategy for Parkinson's disease and other synucleinopathies.

Automated summary

Experimental evidence suggests that deficiency of copper transporter 1 can mitigate the pathology mediated by alpha-synuclein, offering a new research direction for therapeutic strategies aimed at Parkinson's disease and other synucleinopathies.