the role of the parkinsons disease gene park9 in essential cellular pathways and the manganese homeostasis network in yeast帕金森病基因的作用park9必不可少的细胞通路和锰在酵母体内平衡网络.pdfVIP

The Role of the Parkinson’s Disease Gene PARK9 in Essential Cellular Pathways and the Manganese Homeostasis Network in Yeast 1,2 2 2 3 1 Alessandra Chesi , Austin Kilaru , Xiaodong Fang , Antony A. Cooper , Aaron D. Gitler * 1 Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, California, United States of America, 2 Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 3 Garvan Institute of Medical Research, University of New South Wales, Sydney, New South Wales, Australia Abstract YPK9 (Yeast PARK9; also known as YOR291W) is a non-essential yeast gene predicted by sequence to encode a transmembrane P-type transport ATPase. However, its substrate specificity is unknown. Mutations in the human homolog of YPK9, ATP13A2/ PARK9, have been linked to genetic forms of early onset parkinsonism. We previously described a strong genetic interaction between Ypk9 and another Parkinson’s disease (PD) protein a-synuclein in multiple model systems, and a role for Ypk9 in manganese detoxification in yeast. In humans, environmental exposure to toxic levels of manganese causes a syndrome similar to PD and is thus an environmental risk factor for the disease. How manganese contributes to neurodegeneration is poorly understood. Here we describe multiple genome-wide screens in yeast aimed at defining the cellular function of Ypk9 and the mechanisms by which it protects cells from manganese toxicity. In physiological conditions, we found that Ypk9 genetically interacts with essential genes involved in cellular trafficking and the cell cycle. Deletion of Ypk9 sensitizes yeast cells to exposu