A new computational approach for analyzing complex datasets shows that as disease progresses, neurons and astrocytes lose the ability to maintain homeostasis. The ‘Geomic’ approach can be applied to other diseases, authors say.
The analysis yielded a trove of specific gene networks governing molecular pathways that disease researchers may now be able to target to better sustain brain cell health amid the devastating neurodegenerative disorder, said co-senior author Myriam Heiman, Associate Professor in MIT’s Department of Brain and Cognitive Sciences and an investigator at The Picower Institute for Learning and Memory. Christian Neri of the Sorbonne’s Centre National de la Recherche Scientifique is the co-senior and co-corresponding author of the study published in eLife.
«If we can maintain the expression of these compensatory mechanisms, it may be a more effective therapeutic strategy than just trying to affect one gene at a time,» said Heiman, who is also a member of the Broad Institute of MIT and Harvard.
In the study, the team led by co-corresponding author Lucile Megret created a process called «Geomic» to integrate two large sets of data from Heiman’s lab and one more from UCLA researcher William Yang. Each dataset highlighted different aspects of the disease, such as its effect on gene expression over time, how those effects varied by cell type, and the fate of those cells as gene expression varied.
Geomic created plots of the data that mapped differences pertaining to 4,300 genes along dimensions such as mouse age, the extent of Huntington’s-causing mutation, and cell type (certain neurons and astrocytes in a region of the brain called the striatum are especially vulnerable in Huntington’s). The plots took the form of geometric shapes, like crumpled pieces of paper, whose deformations could be computationally compared to identify genes whose expression changed most consequentially amid the disease. The researchers could then look into how abnormal expression of those genes could affect cellular health and function.
Big breakdowns
The Geomic analysis highlighted a clear pattern. Over time, the cells’ responses to the disease pathology — linked to toxic expansions in a protein called Huntingtin — largely continued intact, but certain highly vulnerable cells lost their ability to sustain gene expression needed for some basic systems that sustain cell health and function. These systems initially leapt into action to compensate for the disease but eventually lost steam.
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Materials provided by Picower Institute at MIT. Note: Content may be edited for style and length.