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March 24, 2009

Systems Biology Approach Models Degenerative Brain Disease Progression in Mice

  • Researchers at the Institute for Systems Biology (ISB) and the McLaughlin Research Institute took a systems biology approach and have modeled the progression of degenerative brain diseases that are caused by misfolded proteins called prions.

    The team tracked global gene expression in the brains of eight distinct mouse strain–prion strain combinations at 10 different timepoints during disease progression. The aim was to capture the effects of prion strain, host genetics, and PrP concentration on disease incubation time.

    Subtractive analyses exploiting various aspects of prion biology and infection identified a core of 333 differentially expressed genes (DEGs) that appeared central to prion disease. DEGs were mapped into functional pathways and networks reflecting defined neuropathological events and PrP replication and accumulation.

    This enabled the identification of novel modules and modules that may be involved in genetic effects on incubation time and in prion strain specificity. They were also able to determine about 100 encoded aspects of this disease that were previously unknown. The identification of those RNAs also enabled researchers to discover and describe four biological networks that explain nearly every known aspect of prion disease, and three of the four biological networks are involved in human neurodegenerative diseases such as Alzheimer’s and Huntington’s diseases.

    Based upon the analysis of the disease-perturbed networks, the scientists were also able to identify several protein blood biomarkers that indicate the presence of prion disease prior to the development of symptoms.

    The studies were based on approximately 30 million measurements, which required the researchers to develop a series of new software programs for analyzing, integrating, and modeling these extensive amounts of data. Findings appear online March 24 in Molecular Systems Biology in a paper titled, “A systems approach to prion disease.”

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