Poster L11 - "Pathway Engineering for Uncovering New Druggable Connections in Neurodegenerative Diseases"

Introduction: Neurodegenerative diseases are an area of high unmet need that is especially challenging given imperfect animal models and unclear information about the mechanisms driving disease pathology. In other diseases, pathways analysis, coupled with the electronic health record, has uncovered unexpected effects using data from real-world settings. Thus, there is an opportunity to extend those approaches to neurodegenerative diseases. Our prior discovery in several neurodegenerative diseases’ patients required curated, high-quality patient data for successfully deriving novel pathways. However, the utility of pathway-based predictions depends on successful pathway engineering, or the derivation of pathway lists that sufficiently represent the disease biology.

Materials and

Methods: Initially, we utilized publicly accessible pathways (i.e., gene lists) from DisGeNet, an aggregate database of gene-phenotype associations. The database was initially utilized to obtain gene lists linked to Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS). DisGeNet includes around 3397 genes associated with AD, and 1114 genes linked to ALS. Pathway optimization techniques reduce the pathway gene list by requiring pathway proteins to have functional connections. We specifically used the Prize-Collecting Steiner Forest (PCSF) because it has successfully identified coherent pathways in multiple systems biology analyses. We generated Prize-Collecting Steiner Forest (PCSF) networks for the complete and highest-ranked genes (GDA-modified gene lists) from DisGeNet for two neurodegenerative diseases, Alzheimer’s Disease (AD) and Amyotrophic Lateral Sclerosis (ALS). Following that, we performed a gene ontology (GO) enrichment analysis on the datasets using GOATOOLS to identify significant biological processes and pathways involved in each disease.

Results, Conclusions, and Discussions: Overall, we discovered that optimization algorithms refined all disease gene lists and maintained disease-relevant functional terms. Upon applying the PCSF algorithm to the datasets, we initially compared the PCSF pathway for AD and ALS. The AD final forest comprises 3120 nodes in the full list and 999 nodes in the GDA-modified gene list. The final forest for ALS comprises 1197 nodes for the full list and 296 nodes for the GDA-modified gene list, representing diverse chemical constituents (Fig.1 and Table 1). Following the utilization of GO enrichment, we have identified several shared characteristics and distinctions: A fundamental concern for cellular stress responses, metabolic control, and the balance between cell survival and death is shared by both ALS and AD. Both diseases indicate the involvement of inflammation and immune responses as double-edged swords, which is indicative of a similar pathway that has the potential to be regulated for therapeutic benefit (Table 2). Certain GO terms that are specific to ALS highlight the disease's emphasis on the preservation of motor neurons, synaptic function relevant to motor control, and specialized immunological regulation. In contrast, AD's pathways might be more centered around cognitive function preservation, amyloid-beta, and tau pathology management, and maintaining neural network integrity. Using publicly derived pathways with pathway optimization algorithms discovered compact pathway definitions enriched for disease-relevant processes. This initial finding demonstrates further potential for developing network algorithms predictive of new treatment opportunities in neurodegenerative diseases. Future work will extend this to additional neurodegenerative diseases and test network predictions in the electronic health record.

Acknowledgements (Optional): I would like to thank Dr. Jennifer L. Wilson for her support, as well as the entire team at the Lab for Understanding Network Effects (LUNE), including Mohammad, Emily, Anjali, and Youzi. Their hard work in conducting research and their assistance have been invaluable.