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The new findings affirm a key role for mitochondrial integrity and implicate key genes such as Ndufb10, whose diminished expression may undermine the cell’s network of genes supporting the system. Last year, Heiman’s lab published a study in Neuron showing that in some Huntington’s-afflicted neurons, RNA leaks out of mitochondria provoking a misguided and immune response that leads to cell death. One of the biggest such breakdowns in an especially vulnerable cell type, Drd-1 expressing neurons, was maintaining the health of energy-producing components called mitochondria. These systems initially leapt into action to compensate for the disease but eventually lost steam. 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. The Geomic analysis highlighted a clear pattern. The researchers could then look into how abnormal expression of those genes could affect cellular health and function. 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. 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). 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. 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 University of California at Los Angeles researcher William Yang. “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,” says Heiman, who is also a member of the Broad Institute of MIT and Harvard. 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. 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, says 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.

Using an innovative computational approach to analyze vast brain cell gene expression datasets, researchers at MIT and Sorbonne Université have found that Huntington’s disease may progress to advanced stages more because of a degradation of the cells’ health maintenance systems than because of increased damage from the disease pathology itself.

A new computational approach for analyzing complex datasets shows that as disease progresses, neurons and astrocytes lose the ability to maintain homeostasis.