PgmNr Y3142: An Integrated platform to characterize neurodegenerative disease associated proteins in yeast.

Authors:
S. Ju; S. Chen; A. Koesters; E. Hayden; Q. Zhong


Institutes
Wright State University, Dayton, OH.


Keyword: Genomics

Abstract:

The molecular underpinnings of neurodegenerative disease are gradually emerging following biochemical characterization of protein aggregates in disease tissues, and the identifications of causal genes in certain familial forms of neurodegenerative disorders. With the vast majority of disease cases being sporadic and causes unknown, however, our understanding of neurodegeneration remains vastly incomplete. Becoming increasingly appreciated is also the difficulty to evaluate the extent to which a given risk factor identified in human genomes may alter susceptibility of any individual to a specific type of neurodegenerative disorder. This is largely due to a critically missing aspect of our understanding of neurodegenerative disease from the perspective of complex networks of gene-gene interactions. Such networks may consist of genes with causal or modifier effects and interactions that can be specifically targeted by gene mutations. Here we present three proof-of-principle studies using yeast as a model system to map and characterize biochemical and genetic interactions of neurodegenerative disease-associated proteins. Our studies demonstrate the feasibility to i) systematically profile functional alterations of human gene alleles associated with neurodegenerative disease; ii) to rapidly identify, at the genome scale, genes that exert effects the disease-associated protein aggregation and toxicity at the cellular level; and iii) to measure changes in protein-protein interactions by both disease-causing and putative mutations. Our long-term goal is to interpret phenotypic consequences of genetic variations associated with neurodegenerative disease from the global integrated network perspective.