DiGtoP - From Disease Genes to Protein Pathways

Human genetics research has recently identified mutants in numerous genes that can be linked with disease, including Alzheimer´s and Parkinson´s disease, schizophrenia, cancer, and diabetes. Now the physiological meaning of these mutations and their contributions to the onset of diseases must be identified. This can be achieved by the identification of protein interactions (of the Proteome) of the disease genes. Contrary to the genome the proteome is not a stable structure, but a dynamic entity which may vary from cell to cell and species to species. However, there is a stable nucleus lying behind the proteome of each gene, which can be mapped. The goal of DiGtoP (short for „From Disease Genes to Protein Pathways“) was to diagnose, by the invention of new methodology in proteomics, protein networks that are causal for disease onset.

The DiGtoP consortium consists of nine scientific subprojects with outstanding complementary expertise which elaborate in close interaction the network data of pathological protein interaction partners. Therefore, disease associated genes are tagged with a fluorescence marker (up to now more than 700 genes) to observe their localisation and dynamics in the living cell. This marker serves to determine interaction partner by means of mass spectrometry in a variety of cell types and organs (until now almost 2.000 measurements). The localisation data and interaction partner serve to set up a unique database, in which all data collected are registered and protein networks can be made visible visually. The resulting new hypotheses regarding the molecular basis of the genesis of disease were genetically validated. The data illustrate that distinct protein networks play a role in the development of various diseases or perhaps even are the basis for the often observed co-morbidity between diseases. These findings enable to identify novel target proteins which are of importance to therapeutic development. Previously unknown protein complexes which are important for disease development have already been identified, just as for the hereditary spastic paraplegias (HSP).
Information about the ongoing research is provided on the DiGtoP-homepage (www.digtop.de)

Figure: mES cell with GFP-tagged target gene (Trp53) after targeting in subproject 3 (fixed and stained with anti-GFP antibody). Green: GFP-tagged Transgen, red: A-tubulin, blue: DNA. Picture: Ina Poser/Tony Hyman (Max Planck Institute of Molecular Cell Biology and Genetics, Dresden (subproject 4)


Additional relevant Internet links:
www.eummcr.org