Modeling ALS progression by applying neuroinformatics to a novel in vitro human 3D tri-culture model of the disease

A growing body of evidence suggests that other cell types within the brain influence motor neuron health and survival. Microglia, for example, are the immune cells of the brain that usually play a protective role, but if altered, can become toxic to motor neurons. Astrocytes are another type of specialized support cell within the brain with a wide range of functions, and when these cells don’t function properly the health of motor neurons suffer.

To properly model ALS in the lab, understanding the complex interplay between these various cell types is key. With this grant, Dr. Durcan will create a three-dimensional (3D) model of ALS, called a spheroid, using induced pluripotent stem cells (iPSCs). iPSCs have become an invaluable tool when studying neurodegenerative disease as these cells retain the genetic information of the patient who donated them and can be transformed into motor neurons or any other cell type, such as microglia or astrocytes.

The spheroids developed will represent a variety of familial forms of ALS (SOD1, TARDBP and C9ORF72), as well as sporadic ALS and healthy controls. These models will be analyzed using different assays to study the microglia-astrocyte interplay in ALS, its influence on neuronal health, and how this differs between the various forms. In collaboration with Dr. Iturria-Medina, an expert in neuroinformatics (a research field that focuses on analyzing neuroscience data through computational models), the data obtained will also be used to develop prediction models that may be able to uncover different patterns of progression for different forms of ALS.

By combining an advanced 3D model of ALS and powerful neuroinformatics, the team hopes to gain a better understanding of how neuroinflammation may contribute to ALS, and whether progression may differ depending on the type of ALS being studied. In the future, the team plans to build upon this work to incorporate other cell types into the spheroids and ultimately use these models to study treatment response for new ALS therapies.