The role of Alfy in neurodegeneration

The neurodegenerative disorders Alzheimer's and Huntington's disease are serious and fatal illnesses, currently with no treatments or clear diagnostic tools available. To be able to develop new drugs and diagnostic tools, detailed knowledge is crucial. Al though there have been a number of important findings in this field recently, the image is far from complete. As an organism ages, an increasing amount of proteins are aggregated and accumulate in cells. Neurodegenerative diseases are characterized by abn ormally high amounts of aggregated proteins accumulating in the nerve cells. Such aggregates have been shown to be removed by a process called autophagy, meaning self-eating. We have found that a protein called Alfy is required for the aggregates to be re moved by autophagy and more importantly that Alfy overexpression leads to protection in a neuronal and Drosophila model of poly-glutamine toxicity. Alfy shuttles between the nucleus and the cytosol in the cells, and localizes to aggregates both places. Ou r main objective of this project is to find out how Alfy is involved in removal of aggregated proteins. More specifically; how does it interact with the autophagic membranes? Can Alfy be a rate limiting protein in these diseases? What is the role of its n uclear shuttling? A main challenge of our work is to confirm our biochemical and cell culture findings in physiological relevant model organisms. In collaboration with Dr. Yamamoto at the Columbia University, NY, we will investigate the role of Alfy in cl earance of nuclear and cytoplasmic inclusions, using primary neurons, as well as Alfy transgenic and knock out mice in combination with mice models of neurodegenerative diseases. Our new findings could be of major importance both for diagnostic tools and for development of new drugs against the diseases.