Genetic Analysis of Copper Toxicity Mechanisms in iPSC-derived Human Neurons

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DESCRIPTION (provided by applicant): Copper is a powerful toxic oxidant for neurons whose free levels must be tightly controlled. It is also an essential micronutrient necessary for neurona enzymatic reactions, such as neurotransmitter and neuropeptide synthesis. The importance of copper to neuronal cells is illustrated by Menkes disease, an X-linked genetic disorder characterized by neuronal tissue copper starvation, altered neuronal polarity, and cell survival phenotypes. The precise cellular mechanisms underlying these copper- dependent neuronal phenotypes remain unknown and constitute the focus of this application. The gene affected in Menkes disease, ATP7A, is a Golgi localized protein that loads copper into secretory proteins. This fact suggests that Menkes disease phenotypes result from alterations in the entire copper sensitive secreted proteome. We propose to test this hypothesis by comprehensively identifying the human neuronal copper-sensitive secreted proteome in human induced pluripotent stem cells (iPSCs) differentiated into neurons. We will test the participation of the copper-sensitive proteome in the progression and severity of Menkes disease neuronal pathology. Such knowledge will contribute to our understanding and development of therapeutics in Menkes disease as well as diseases affected by copper availability, such as Alzheimer's disease.