Increasing evidences show that neurodegenerative diseases such as Parkinsons disease (PD), Alzheimers disease (AD), Huntingtons disease (HD), amyotrophic lateral sclerosis (ALS), and prion diseases share common cellular and molecular mechanisms including protein aggregates inclusion body formation.A novel genome-wide, imaging-based screening method was set up to investigate inclusion body formation machineries.This system integrates robotic sample handling system, autofocus approaches, and automatic image acquisition, processing, quantification, and scoring approaches.By using this system, markers (Hsp104-GFP and synphilin-1-GFP) of different inclusions are incorporated into yeast deletion (about 4600 mutants) and essential gene temperature sensitive (TS) collection (about 800 alleles).Inclusion phenotypes such as the rate of inclusion body formation, aggregate morphology, and resolution rate were scored for in each mutant.We found 176 mutants showing a defect in inclusion body formation, which means that instead of forming one or two large inclusions, these mutants form multiple aggregates.An in-depth study of the function of these components in aggregate deposition and inheritance is ongoing.In addition, to continue with our previous study on the human Huntingtons disease proteins, we have started another project to identify components required to detoxify the Huntington mutant proteins (Htt103Q and Htt103QP).The new image screening approach in combination with bioinformatics and classical molecular and genetics methods will make it possible to identify and characterize potential hits in both yeast and humanized model systems.This unbiased screening approach should be able to identify almost all components and pathways involved in different inclusion body management processes.