Copper is essential for normal brain function, but must be strictly regulated as either too much or too little copper leads to dysfunction. This is evident in many neurodegenerative diseases, most obviously in Wilson’s disease and Menkes disease driven by copper overload and copper deficiency, respectively, but also in Alzheimer’s disease, Parkinson’s disease and motor neuron disease. The latter diseases involve a misregulation of copper resulting in cellular deficiency or insufficiency. We have developed a novel strategy for targeting neurodegeneration aimed at correcting copper homeostasis. Our preclinical work demonstrates that CuII(atsm), a copper delivery drug, alleviates symptoms and extends survival in multiple animal models of Parkinson’s disease and motor neuron disease. This suggests that copper dysregulation may be driving neurodegeneration. On the basis of this work, CuII(atsm) is under investigation in a Phase I clinical trial in motor neuron disease patients (NCT02870634). However, the exact mechanism of action of CuII(atsm) is unclear. One robust feature of CuII(atsm) treatment evident in our preclinical work is the conspicuous attenuation of both oxidative stress and neuroinflammation. Consistent with these outcomes is the activation of Nrf2 signalling. Nrf2 is a transcription factor that regulates hundreds of antioxidant genes and is impaired in neurodegeneration. My work has found that CuII(atsm) activates neuroprotective Nrf2 signalling in vitro and in vivo models of motor neuron disease. Nrf2 is an attractive therapeutic target as its activation boosts the endogenous antioxidant and anti-inflammatory systems within cells. Indeed many studies have found that pharmacological or genetic activation of Nrf2 is protective in models of neurodegeneration, and is targeted by clinicallyapproved therapies. That a copper delivery drug activates Nrf2 and improves symptoms in models of neurodegeneration suggests that the Nrf2 insufficiency and resulting oxidative stress and neuroinflammation evident in neurodegeneration may be driven by copper dysregulation. Hence this provides a druggable disease-modifying therapeutic target.
Audience take away:
• Copper is an essential element for normal brain function. Compelling evidence demonstrates that copper is dysregulated in neurodegeneration, yet this is an often overlooked aspect of neurodegeneration. This presentation will provide the audience with critical insight and recognition of its importance.
• The audience will also gain an understanding of the importance and effectiveness of alleviating targeting inflammation and oxidative stress by targeting endogenous mechanisms.
• Finally, this presentation exhibits our exciting findings generated with a copper drug, showing that increasing copper is beneficial in neurodegeneration in contrast to the pervading view that increasing copper is detrimental.