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Exploring Amyotrophic Lateral Sclerosis (ALS) with PercayAI’s AI Tools 

 

Part III: Using mouse models to understand ALS

August 10,2020

Welcome to our newest blog series where we investigate Amyotrophic Lateral Sclerosis (ALS) using our AI knowledge mapping tools. Check back for our next installment, in which we analyze transcriptomics from spinal cord samples collected from patients as well as a mouse model.

New to our ALS series? Read part one here. 

In this post, we will continue to explore publicly available datasets surrounding Amyotrophic Lateral Sclerosis (ALS), a devastating neuromuscular degenerative disease for which there is no cure. If you’re not a neuroscientist and want to quickly get up to speed on the important biological themes in ALS, you may find the knowledge map in our first post helpful. Our second post discussed familial versus sporadic ALS, and used PercayAI’s concept-level comparison tool to identify biological processes and pathways that are similar between these two subsets of the disease. 

 

In our third post of the series, we will analyze a mouse model of ALS. As any preclinical researcher is well aware, mouse models provide powerful and rapid insights into human disease, but can often lead scientists astray if a result does not translate to humans. We’ll use our concept-level comparison tool to identify aspects of the mouse ALS model that are conserved in human familial ALS. This workflow can be used for any area of translational research.

 

Examining a mouse model of familial ALS: The SOD1 transgenic mouse

One of the commonly used tools to study familial ALS is a transgenic mouse model expressing the G93A mutation in the Cu,Zn-superoxide dismutase (SOD1) gene, which is a known mutation causing ALS in humans. We used transcriptomics data from a study performed by Lukas et al. to better understand the biological processes displayed in this mouse model.

The knowledge map shows the following upregulated processes in the SOD1 Mouse:

  • Growth and differentiation processes in orange

  • Metabolism and adipogenesis in purple

  • Regulation of RNA/proteins in green

  • Immune/inflammatory processes in blue

The knowledge map shows the following downregulated processes in the SOD1 Mouse:

  • Autophagy in blue

  • Stress response and homeostasis in red

  • Neuronal signaling pathways in green

  • Gene/protein regulation in orange

Key Takeaways:

The upregulation of genes related to myogenesis and hematopoietic stem cells may be a compensatory response to the damage resulting from SOD1 impairment. The large cluster of lipid metabolism and adipogenesis related Themes may be related to changes in axon myelination, a process that is negatively affected in ALS. The adipogenesis signature may also be related to a compensatory regeneration process, as fibro-adipogenic progenitors are shown to expand in response to muscle injury. 


Among the downregulated themes are several processes involved in the cellular stress response and maintaining homeostasis, defects in which would predispose an organism to further damage. The large cluster of downregulated autophagy-related themes (blue) represent another critical defect that may further contribute to damage in ALS. The role of autophagy in ALS is an area of ongoing research.

 

What aspects of familial ALS are represented in the SOD1 mouse model?

To understand which aspects of the mouse model are most likely to translate to humans, and therefore may be the best areas to target in preclinical studies, we performed a concept-level comparison of the mouse model and familial ALS knowledge maps. (For a detailed look at human ALS datasets, both familial and sporadic forms, take a look at our previous blog post.

The knowledge map shows the following upregulated processes shared by familial ALS patients and the SOD1 Mouse:

  • Stress response in green

  • Growth/differentiation in purple

The knowledge map shows the following downregulated processes shared by familial ALS patients and the SOD1 Mouse:

  • Growth/differentiation in purple

  • Defense/homeostasis in red

Key Takeaways:

Many of the most prominent signatures of human familial ALS are shared with the SOD1 mouse, demonstrating that it is an effective model for studying human disease. Both the up- and downregulated knowledge maps display growth/differentiation themes (purple). Of the upregulated themes, many are related to lipids (e.g., adipocyte related and PPAR signaling), which may represent compensatory responses in myelination or regeneration, as mentioned above. Of the downregulated themes, there are signatures related to cell differentiation/maturation, potentially demonstrating a loss of cellular plasticity needed for maintenance and repair in ALS. 

 

The other overarching theme in both up- and downregulated knowledge maps is stress response (up) and defense (down). These are conceptually similar, but demonstrate that while some stress responses (such as the ubiquitin proteasome system and inflammation) are still activated in response to damage occurring with disease progression, other crucial processes are weakened. Downregulation of genes associated with astroglia and peroxisomes suggest an inability to maintain some of the most important neuronal defense/maintenance cells (astroglia) and an insufficient response to the oxidative stress resulting from the SOD1 mutation.

 

The most prominent conserved theme between the human and mouse datasets is the upregulation of genes involved with myogenesis. We hypothesize that this represents a compensatory response from muscle damage that occurs with ALS. If you have other insights or ideas, please reach out.

 

Let us know what you think

The findings highlighted in this post just scratch the surface. If you have additional thoughts on these analyses, see something interesting we missed, or have any other feedback on the results from this post, we’d love to hear from you!

*We are launching this webpage to share knowledge maps to encourage hypotheses generation. We invite you to share your ideas, insights, and feedback (“Feedback”) to help us create hypotheses in connection with therapies, treatments, and solutions. Please click on the links below which cover our Right to Use Feedback, and important Disclaimers. By submitting Feedback, you agree that you have read and agree to these terms. Thank you for your participation in this project.

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