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The basic cellular health system is exhausted by Huntington’s disease, new analysis shows

Geomic is based on dimensions such as mouse age, degree of mutations that cause Huntington’s disease, and cell type (specific neurons and astrocytes in a region of the brain called the striatum are particularly vulnerable to Huntington’s disease). I made a plot of the data that mapped the differences for 4,300 genes). The plot took the form of a crumpled piece of paper-like geometry and the deformations could be calculated and compared to identify the most consequentially altered gene in the disease. Researchers have since been able to investigate how abnormal expression of these genes affects cell health and function. Credit: Sorbonne Université

Researchers at MIT and Sorbonne Université used an innovative computational approach to analyze vast brain cell gene expression datasets, and Huntington’s disease is due to deterioration of the cellular health maintenance system rather than increased damage from the disease. We have discovered that we may go to an advanced stage. Pathology itself.

Miriam Heymann, an associate professor and co-chief author of MIT’s School of Brain Cognition, said the analysis created a mountain of specific genetic networks that govern molecular pathways, leaving disease researchers in a catastrophic neurodegenerative disease. Researchers at the Institute of Science and Picower Learning and Memory have stated that they may be targeted to better maintain the health of brain cells. Christian Neri of the National Center for Scientific Research, University of Sorbonne is a co-senior and co-author of the research presented at. eLife..

“Maintaining the expression of these compensatory mechanisms could be a more effective therapeutic strategy than affecting one gene at a time,” said Heimann, a member of the Broad Institute of MIT and Harvard. Says.

In this study, a team led by co-author Lucile Megret is called “Geomic,” which integrates two large datasets from Heiman’s lab and another from UCLA researcher William Yang. I have created a process. Each dataset highlights various aspects of the disease, such as its effects on gene expression over time, how those effects change with cell type, and the fate of those cells as gene expression changes. Did.

Geomic is based on dimensions such as mouse age, degree of mutations that cause Huntington’s disease, and cell type (specific neurons and astrocytes in a region of the brain called the striatum are particularly vulnerable to Huntington’s disease). I made a plot of the data that mapped the differences for 4,300 genes). The plot took the form of a crumpled piece of paper-like geometry and the deformations could be calculated and compared to identify the most consequentially altered gene in the disease. Researchers have since been able to investigate how abnormal expression of these genes affects cell health and function.

Major breakdown

Geographic analysis has highlighted clear patterns. Over time, the cell’s response to the pathology of a disease associated with the toxic growth of a protein called huntingtin remained largely intact, but certain highly vulnerable cells maintain cell health and function. It has lost the ability to maintain the gene expression required for its basic system. These systems initially took action to make up for the illness, but eventually lost steam.

One of the greatest destructions in Drd-1-expressing neurons, a particularly fragile cell type, was to maintain the health of an energy-producing component called mitochondria. Last year, Heiman’s lab published a study in neurons showing that RNA leaks from mitochondria in some of the neurons suffering from Huntington’s disease, causing a false immune response that leads to cell death. New discoveries confirm an important role in mitochondrial integrity and suggest important genes such as Ndufb10 whose reduced expression may weaken the cellular network of genes that support the system.

The geomic approach also highlighted a particularly dramatic reduction in the expression of multiple genes in the pathways governing endosome regulation in Drd-1 neurons and astrocytes. This is an important process in determining where a protein goes and when it is broken down in the cell. Again, important genes such as Rab8b and Rab7 have emerged as causes within the broader gene network.

Researchers continued to validate some of their major findings by confirming that significant changes in gene expression were also present in postmortem samples of brain tissue in patients with human Huntington’s disease.

Mitochondrial integrity and endosome regulation are two particularly powerful examples, but Heimann says there are many other examples in this study. The Geomic source code and all the data and visualizations it generates are published on the website created by the author.

“We have created a database of future targets to investigate,” Heyman said.

“This database provides an accurate basis for studying ways to adequately restore brain cell compensation in Huntington’s disease, and perhaps other neurodegenerative diseases that share a common compensatory mechanism with Huntington’s disease,” Neri added. To set. “

Of these, important may be regulators of gene transcription in these affected pathways, Heimann said.

“One of the promising directions for the future is that some of these genes are transcription factors among the genes involved in these network effects,” she said. “They may be an important goal to regain a declining compensatory response.”

A new way to study illness

Researchers first applied Geomic’s “shape deformation analysis” method to Huntington’s disease, but it is equally useful in studying neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and other brain diseases. The authors state that there is.

“This is a new approach for studying system-level changes, as well as focusing on specific pathways and specific genes,” Heiman said. “This is a very good proof of principle and we hope that this type of methodology can be applied to the study of other genomic data from other disease studies.”


Huntington’s disease nerve fragility associated with mitochondrial RNA release


For more information:
Lucile Megret et al, Shape Deformation Analysis reveals the temporal dynamics of cell type-specific homeostasis and pathogenic response to mutant huntingtin. eLife (2021). DOI: 10.7554 / eLife.64984

Journal information:
eLife

Provided by Massachusetts Institute of Technology

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The basic cellular health system is exhausted by Huntington’s disease, new analysis shows

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