PD BEL Model
The discovery and development of new treatments for Parkinson’s disease (PD) requires a profound mechanistic understanding of the disease. We used a model-driven approach supporting the systematic identification of putative disease mechanisms. By systematically curating knowledge from the PD literature, we have developed a knowledge assembly using Biological Expression Language (BEL) that comprises causal and correlative relationships between biomolecules, pathways, and clinical readouts. We focused especially on PD epigenetics, mitochondrial dysfunction, SWEDD SNPs model and selected PD biomarkers like PDE4D, METRNL, HSD17B10.
This PD knowledge assembly is represented as a network that contains 1.424 nodes, 2.690 edges and comprises the knowledge of almost 432 citations, resulting in 2.236 BEL statements. Furthermore, this knowledge assembly is the foundation of NeuroMMSig, the catalog of mechanisms in AETIONOMY.
In the following screenshot the PD BEL model is shown representing entities (genes, proteins, …) as nodes and relations (associations) as edges as the computable knowledge model for PD, coded in BEL.
The most essential pathways such as "PINK1 subgraph" and "Ubiquitin subgraph" play a role in combination. PINK1 and Parkin’s gene products work together to govern mitochondrial damage, thus affecting the "Mitochondrial subgraph". In a damaged mitochondrion, Parkin ubiquitinates the outer mitochondrial membrane proteins to trigger selective autophagy. Thus, "Ubiquitin subgraph" is activated in the process (Pickrell and Youle, 2014). A protein, alpha-synuclein is found in all Lewy bodies in a clumped form that cells can’t break down. Hence, "Synuclein subgraph" also plays a major role, causing disruption of homeostasis and neuronal death (Leonidas, 2012). Furthermore, polymorphic length and SNP variations in SNCA have repeatedly been shown to be among the most significant PD risk factors. ATP13A2 and PARK9 mutations have been found to cause an atypical form of PD named Kufor-Rakeb syndrome (Klein and Westenberger, 2012). This leads to several lysosomal alterations such as decreased proteolytic processing of lysosomal enzymes, reduced degradation of lysosomal substrates, autophagy and cell death. Pathogenic mutations in the LRRK2 gene cause a significant proportion of clinically typical, late-onset PD. The "LRRK2 subgraph" can also be linked to various possible pathogenic mechanisms of PD such as α-synuclein, tau, inflammatory response, oxidative stress, mitochondrial dysfunction, synaptic dysfunction as well as autophagy-lysosomal system (Li., et al 2014).