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598e

Systems Biology Analysis of Neurodegenerative Diseases

Zheng Li1, Ayla Ergun1, Benjamin Wolozin2, and James J. Collins1. (1) Biomedical Engineering, Boston University, 44 Cumminton St, Boston, MA 02215, (2) Depts. of Pharmacology and Neurology, Boston University School of Medicine, 715 Albany St, R-614, Boston, MA 02118

Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, characterized by degeneration of motor neurons in brain and spinal cord, leading to muscle atrophy and eventually death. Extensive studies have been undertaken to understand the pathogenesis of ALS. However, the underlying mechanisms of the selective degeneration of motor neurons in ALS are still incompletely understood today. It is the objective of this study to apply systems biology approaches to integrate interactome data with microarray gene expression profiles to identify the causal factors of ALS.

The interaction data including protein-protein, protein-DNA interactions of both human and mouse were collected from public databases such as NCBI. The microarray gene expression profiles of both ALS patients and mice model were obtained from GEO database. The interaction data was used to reconstruct the underlying network and gene expression profiles were applied to identify the causal pathways that were transcriptionally differentiated in ALS patients or mice model. Simulated annealing was applied to search the subnetwork with the highest score based upon transcription profile. Not surprisingly, human studies revealed an enriched pattern of cell death, neurodegeneration and inflammation. However, human samples were obtained from the patients at the end stage of the disease, which may not be informative about the causal pathways. To obtain a more complete picture of which pathways are altered within degenerating motor neurons and identify which stage of the disease these changes happen, we obtained time course gene expression profile from transgenic SOD93A mice model. Three specific stages of disease progression were evaluated, correlating with the initiation of molecular changes (60 days), the onset of muscle weakness and motor neuron loss (90 days) and late stage time point of robust motor neuron pathology (120 days). The early time point analysis indicated that the pathways such as insulin signaling, EGF signaling, PI3K-AKT, TGF signaling and antioxidant ARE-NRF2 pathway were involved in the initiation of the disease. The late stage of the mice model resembles the human studies with pathways such as apoptosis being enriched. The transcription factors and microRNAs enriched in the identified gene modules were also studied. Potential therapeutic targets were predicted and validated either with published literature or with experiments. It is also discussed how to design combinations of multiple therapeutic targets perturbations to ameliorate ALS phenotype.