Optimizing human post-mortem brain tissue gene expression profiling in Parkinson's disease and other neurodegenerative disorders: from target "fishing" to translational breakthroughs.

Insights on the etiopathogenesis of common neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD) have been largely based on the discovery of gene mutations in genetically determined forms. Although these discoveries have been helpful in elucidating the basic molecular pathogenesis of familial forms, they represent a small fraction of cases, leaving the large majority classified as idiopathic. In the postgenomic era, brain tissue gene expression profiling has allowed relative quantitative assessment of thousands of genes simultaneously from one tissue sample, providing clues for novel candidate genes and processes implicated in neurodegenerative disorders. Some remain critical of "fishing expedition" science, but gene expression profiling is a discovery-based procedure well suited for the study of largely idiopathic and multifactorial diseases. However, the technology is still under development, and many methodological and biological aspects contribute to the heterogeneous results obtained from gene expression profiling. In this Review, we discuss the advantages and limitations of this technology in simple terms and identify the key variables that influence/limit gene expression profiling-derived translational breakthroughs in neurodegenerative diseases. (c) 2007 Wiley-Liss, Inc.