Analysis of genetic factors influencing alpha-synuclein toxicity
Community Fast Track, 2003
Parkinson's disease is a devastating disease that robs its victims of the ability to direct and control normal movement. These symptoms result from the death of a particular class of nerve cell in the brain that secretes a chemical messenger called dopamine. A variety of studies have incriminated the protein alpha-synuclein as a primary culprit in this disease, but the reasons for alpha-synuclein's toxicity remain elusive. To understand more precisely how alpha-synuclein affects nerve cells, studies were recently carried out with a single-celled organism that nevertheless shares many basic features of a human cell, the common baker's yeast. A modified version of baker's yeast was created that produces human alpha-synuclein protein, and this yeast strain was then used in genetic experiments to identify yeast genes that influence the toxicity of alpha-synuclein. Many of the genes identified in yeast have counterparts in higher organisms, including humans. The goal of the current proposal is to determine whether these genes affect alpha-synuclein toxicity in the context of a functioning brain. We have chosen to address this question in the fruit fly, Drosophila melanogaster, one of the simplest organisms that have dopamine-secreting nerve cells. We have genetically modified fruit flies to produce human alpha-synuclein protein in dopamine-secreting nerve cells and will test whether Drosophila genes similar to those identified in yeast influence the toxicity of alpha-synuclein in these cells. This work may ultimately explain how alpha-synuclein acts to kill dopamine neurons in humans. An understanding of the mechanisms by which alpha-synuclein kills dopamine neurons may make it possible to develop therapeutic strategies to treat and possibly cure Parkinson's disease.
Assistant Professor in the Department of Genome Sciences at University of Washington