Wearing Down of Protective System in Brain May Underlie Huntington’s
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Progression in Huntington’s disease may be due more to a gradual loss of the system that maintains the health of brain cells than to accumulated damage caused by the disease itself, a computational analysis of large and complex datasets suggests.
This analysis, called Geomic, showed that while brain cells most vulnerable to Huntington’s continue to activate a series of compensatory mechanisms to maintain their function and survival in the presence of such damage, these mechanisms eventually wear down.
“If we can maintain the [activity] of these compensatory mechanisms, it may be a more effective therapeutic strategy than just trying to affect one gene at a time,” Myriam Heiman, PhD, a study co-senior author at the Broad Institute of MIT and Harvard and The Picower Institute for Learning and Memory at MIT, said in a university press release.
This Geomic approach allowed the creation of “a database of future targets to probe” in Huntington’s, added Heiman, who is also an associate professor in MIT’s brain and cognitive sciences department.
The study, “Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin,” was published in the journal eLife.
Huntington’s is caused by excessive repeats of a portion of DNA, called CAG triplets, within the HTT gene. They lead to the production of an abnormal and toxic version of the huntingtin protein that affects brain regions responsible for movement, thought, memory, and behavior.
Increasing evidence suggests that advanced progression of neurodegenerative diseases such as Huntington’s is “often associated with a loss of compensatory processes that enable neural circuits to retain robust function even in the presence of some level of cellular dysfunction or loss,” the researchers wrote.
However, “the molecular mechanisms that underlie this loss remain poorly understood on a [molecular] systems level,” they added.
Heiman’s team — working with a team led by Christian Neri, PhD, the study’s other co-senior author at Sorbonne University’s National Centre for Scientific Research, in Paris — developed a new computational approach, Geomic, to integrate three complex molecular and cellular datasets from Huntington’s mouse models.
Each dataset highlighted different aspects of Huntington’s, such as its effect on brain cell gene activity over time, how these effects varied by cell type, and the fate of those cells as gene activity changed.
Geomic generated plots of the data that mapped differences in the activity of 4,300 genes, along with dimensions such as mouse age, the extent of HTT‘s excessive repeats, and cell types (neurons and astrocytes) in the striatum — a brain region greatly affected by Huntington’s. Astrocytes are brain cells that support neuronal function.
These plots took the form of geometric shapes resembling wrinkled pieces of paper, and their deformations could be computationally compared to identify genes whose activity changed the most throughout the disease.
This analysis identified 136 genes involved in disease-associated responses, and 103 genes that underlined a compensatory response to the disease. Importantly, the researchers found that most of these disease-associated and compensatory responses diminished over time in neurons and astrocytes of the striatum.
This suggests that “neuronal decline and death in HD [Huntington’s disease] is primarily caused by the loss of compensatory responses over time, and not by the increase in strength of pathogenic [disease-associated] mechanisms,” the researchers wrote.
Results also showed that Drd-1-producing neurons, an especially vulnerable striatal cell type, and astrocytes shared two compensatory mechanisms whose strength diminished over time.
One was involved in maintaining the health of mitochondria — the cell’s energy source — and the other in the function of endosomes, specialized vesicles responsible for trafficking and recycling molecules within the cell. Notably, problems in mitochondria and in endosomes were previously associated with Huntington’s and other neurodegenerative diseases.
Changes in mitochondria and endosome function appear “as common disease drivers in these cells,” the team wrote.
Some of these major findings were also validated in lab-grown human cells, and in brain tissue samples from Huntington’s patients who had died.
The Geomic approach allowed the identification of “previously undetected molecular patterns and rules that, in specific cell types, may underlie the decreased capacity of neural circuits to cope with the HD process over time,” the researchers wrote.
It also provided “a blueprint to select therapeutic targets for re-instating neuronal resilience and to select biomarker(s) for monitoring whether candidate [therapies] may engage [compensatory] mechanisms for efficacy,” the researchers wrote.
“This database sets a precise basis for studying how to properly reinstate brain cell compensation in Huntington’s disease, and possibly in other neurodegenerative diseases that share common compensatory mechanisms,” Neri said.
“One promising future direction is that among the genes that we implicate in these network effects, some of these are transcription factors,” Heiman said, adding “they may be key targets to bring back the compensatory responses that decline.”
Transcription factors are proteins that regulate the activity of other genes.
Researchers also placed the Geomic source code and data it generated on a publicly accessible website they created, opening their use to others working to advance research in Huntington’s and other neurodegenerative diseases.
“This is a new approach to study systems-level changes, rather than just focusing on a particular pathway or a particular gene,” Heiman said, adding that their study represents a “really nice proof of principle” for this type of methodology.
The study was supported by Sorbonne University, and the CHDI Foundation and National Institutes of Health in the U.S.
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