Recently,a novel mechanism of neurodegeneration was discovered, which involves oxidation of potassium-selective channels (K+ channels) by reactive oxygen species (ROS) leaking out of the mitochondria during the normal aging process. K+ channels are a fundamental class of proteins expressed in virtually any cell and in neurons they play a crucial role for signaling and survival. The fact that these proteins can be modified by ROS during aging prompts the key question as to which are the cellular and molecular mechanisms underlying this novel physiological mechanism.
To address this question, an invertebrate model system will be employed, the nematode Caenorhabditis elegans. Its simplicity, (302 neurons, short life span, powerful genetics) along with powerful tools for laboratory study, including genetics, electrophysiological and optical measurements in native C. elegans neurons, and animal models (i.e. knock-out worms, transgenic animals expressing K+ channel variants etc.) will enable dissection of the basic principles governing oxidation of K+ channels during aging at cellular and molecular level.
Oxygen metabolism is a fundamental biological process which is conserved across species, and growing evidence suggests that ROS can modulate K+ channels in the mammalian brain even though the mechanisms are poorly defined. Therefore the impact of this project is deemed significant at both scientific and educational levels. At scientific level because the elucidation of the mechanisms through which ROS modify K+ channels will provide crucial mechanistic information that will advance the global understanding of the function of neurons in physiological contexts. At the educational level because this project will expose students and postdoctoral fellows to novel and creative concepts, grant them scientific training and provide the basis for their future professional development.
