Disease Maps Community Meeting 2019 - MINERVA tutorial

Table of contents

Important links / Files

  • The website of the Parkinson’s disease map (link)
  • Files with data overlays (braak 1-2, braak 3-4, braak 5-6)
  • MINERVA Platform v13.2 user guide (link)
  • MINERVA Platform quick reference guide (link)

Instructions / Tasks

Introduction to Parkinson’s disease map

Parkinson’s disease (PD) is a neurodegenerative disease involving a complex interplay of environmental and genetic factors. We need to organize and explore the knowledge in this field.

The PD map is a diagrammatical, standardized representation of molecular mechanisms of PD. It can be linked to bioinformatics tools for easy exploration of its contents (Fujita et al., Molecular Neurobiology, 2014). The PD map focuses on neurodegenerative processes of the neuronal system, in particular on the degeneration of dopaminergic neurons of substantia nigra pars compacta. Manually curated interactions are supported by publications in a diagram of roughly 5,000 elements linked by over 2,000 interactions.

The MINERVA Platform allows to explore of this large repository of molecular mechanisms, and enables users to interpret their experimental data and guide content curation via the commenting system (Gawron et al., npj Systems Biology and Applications, 2016).


Task 1: Access experimental overlays with Braak stages

One of the scales categorizing the progression of PD are Braak stages. Dijkstra et al carried out experimental analysis of genes differently expressed in brain tissue of PD patients in different Braak stages. We will use a ready differential gene expression (DEG) dataset, display and explore it in the Parkinson’s disease map.

Goal: display and explore experimental data in the Parkinson’s disease map.

Steps:

  1. Open the PD map
  2. Login to the workshop account, using the login button in the Overlays tab
    login: dmcm19 password: minerva (see hint here)
  3. In the Overlays tab, in the User-provided overlays, select three datasets of Braak stages
  4. Explore the map for areas indicating early markers of Parkinson’s disease (stages 1-2)
  5. Check the coloring of the submap elements
    • in the upper left corner of the map area there are quick links to the PD map submaps (“Submaps” tab)
    • when overlays are switched on, these elements are multi-colored, reflecting the coloring of the underlying submap
    • click on one of the multi-colored submap, click on the button in the left panel to show the submap (see hint here)

Questions:

  1. Which areas are most populated with DEGs?
  2. What is an example of early down-regulated and up-regulated genes?
  3. Which submaps are down-regulated the most in the first Braak stages?


Task 2: Look up drug/chemical/miRNA targets

Steps:

  1. Reset the view: turn off overlays, switch to Pathways and Compartments view, press Clear, center the map (see hint here)
  2. Look for a specific drug: levodopa
    Use Search tab, Drug subtab
  3. Press Clear. look for a specific drug: rotenone
    Use Search tab, Chemical subtab
  4. Look at all interacting drugs for DRD2 receptor
    • Press Clear, find DRD2 on the map (manually or by using search)
    • Click on DRD2, then on the pin of DRD2
    • Tick the box “Show all”
    • For hints check the quick reference guide

Questions:

  1. Could levodopa modulate neuroinflammation?
  2. Why rotenone may not be a good molecule for testing mechanisms of PD?
  3. Is aluminium interacting with DRD2? (hint: check all interacting chemicals)



Task 3: Genetic variants

Steps:

  1. Reset the view: Press Clear, center the map
  2. Go to Overlays tab and switch on the “PRKN variants” overview
  3. Find PRKN on the map (manually or by using search)
  4. Click on PRKN, then on the pin of PRKN
  5. Browse PRKN genetic variants



Task 4: Gene Set Enrichment with plugins

  1. Reset the view: turn off overlays, switch to Pathways and Compartments view, press Clear, center the map (see hint here)
  2. Open the “Plugins” menu in the bottom right corner plugins
  3. Load the GSEA plugin (it takes a while) (see hint here)
  4. Switch on Braak 1-2 overlay, run GSEA (screenshot) and examine the results
  5. Switch on also Braak 3-4 and 5-6 overlays, run GSEA and examine the results

Questions:

  1. What are the pathways enriched in all Braak stages (all datasets switched on), but not in the Braak stages 1-2 only?
  2. What are differences in enriched submaps?


Task 5: Adverse Drug Reactions with plugins

  1. Reset the view: turn off overlays, switch to Pathways and Compartments view, press Clear, center the map
  2. Unload GSEA plugin
  3. Load the Adverse Drug reactions plugin (it takes a while) (see hint here)
  4. See how drug targets change when drugs and adverse reactions are narrowed down by search terms

Questions:

  1. What drugs have “bradykinesia” as a side effect?
  2. What map area is affected by the drug “IMPAVIDO”?