Yeast Screens for Treatment of Human Disease

Abstract

Screening methods for identifying substances that provide therapeutic value for various diseases associated with protein misfolding are provided. Genetic and chemical screening methods are provided using a yeast system. The methods of the invention provide a rapid and cost-effective method to screen for compounds that prevent protein misfolding and/or protein fibril formation and/or protein aggregation which includes numerous neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, Huntington's disease as well as non-neuronal diseases such as type 2 diabetes.

1 .- 68 . (canceled) 
     
     
         69 . A method of screening for a compound that decreases tau associated toxicity, the method comprising:
 providing a yeast cell engineered to express a protein comprising a tau polypeptide;   contacting the yeast cell with a candidate compound; and   evaluating the yeast cell for viability, wherein an increase in viability of the yeast cell as compared to viability of the yeast cell in the absence of the candidate compound indicates that the candidate compound decreases tau associated toxicity.   
     
     
         70 . The method of  claim 69 , wherein the candidate compound is a small molecule or a nucleic acid. 
     
     
         71 . A method of screening for a compound that decreases tau associated toxicity, the method comprising:
 contacting a yeast cell with a candidate compound, wherein the yeast cell expresses a protein comprising a tau polypeptide;   contacting the yeast cell with a toxicity inducing agent; and   evaluating the yeast cell for viability, wherein an increase in viability of the yeast cell as compared to viability of the yeast cell in the absence of the candidate compound indicates that the candidate compound decreases tau associated toxicity.   
     
     
         72 . The method of  claim 71 , wherein the toxicity inducing agent is a carbon source, nitrogen source, chemotherapeutic agent, alcohol, translation inhibitor, NSAID, DNA intercalator, chelator, liposome, antibiotic, vitamin, proteasome inhibitor, anti-oxidant, or reducing agent. 
     
     
         73 . The method of  claim 71 , wherein the toxicity inducing agent is a metal or salt. 
     
     
         74 . The method of  claim 71 , wherein the toxicity inducing agent is a compound that causes oxidative stress. 
     
     
         75 . The method of  claim 74 , wherein the compound that causes oxidative stress is menadione or diamide. 
     
     
         76 . The method of  claim 71 , wherein the candidate compound is a small molecule or a nucleic acid.