The brain is not a passive recipient of injury or disease. Research has shown that when neurons die and disrupt the natural flow of information they maintain with other neurons, the brain compensates by redirecting communications through other neuronal networks. This adjustment or rewiring continues until the damage goes beyond compensation.

This process of adjustment, a result of the brain's plasticity, or its ability to change or reorganize neural networks, occurs in neurodegenerative conditions such as Alzheimer's, Parkinson's and Huntington's disease (HD). As the conditions progress, many genes change the way they are normally expressed, turning some genes up and others down. The challenge for researchers like Dr. Juan Botas who studies HD, has been to determine which of the gene expression changes are involved in causing the disease and which ones help mitigate the damage, as this may be critical for designing effective therapeutic interventions.

In his lab at Baylor College of Medicine, Botas and his colleagues look to understand what causes the loss of communication or synapses between neurons in HD. Up until now, research has focused on neurons because the normal huntingtin gene, whose mutation causes the condition, contributes to maintaining healthy neuronal communication. In the current work, the researchers looked into synapses loss in HD from a different perspective.

In this study we focused on glia cells, which are a type of brain cell that is just as important as neurons to neuronal communication. We thought that glia might be playing a role in either contributing or compensating for the damage observed in Huntington's disease. One class of compensatory changes affected genes involved in synaptic function. Could glia be involved? To answer this question, we created fruit flies that express mHTT only in glia, only in neurons or in both cell types. To investigate whether the reduction of expression of these genes in glia either helped with disease progression or with mitigation, we manipulated each gene either in neurons, glial cells or both cell types in the HD fruit fly model. Then we determined the effect of the gene expression change on the function of the flies' nervous system.
Dr Botas

They evaluated the flies' nervous system health with a high-throughput automated system that assessed locomotor behavior quantitatively. The system filmed the flies as they naturally climbed up a tube. Healthy flies readily climb, but when their ability to move is compromised, the flies have a hard time climbing. The researchers looked at how the flies move because one of the characteristics of HD is progressive disruption of normal body movements.

Our study reveals that glia affected by HD respond by tuning down synapse genes, which has a protective effect. Some gene expression changes in HD promote disease progression, but other changes in gene expression are protective. Our findings suggest that antagonizing all disease-associated alterations, for example using drugs to modify gene expression profiles, may oppose the brain's efforts to protect itself from this devastating disease. We propose that researchers studying neurological disorders could deepen their analyses by including glia in their investigations.
Dr Botas,

 

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