You are here

Title

Downregulating glial genes involved in synapse function protects from Huntington's disease

Featured Faculty

Featured Faculty

A study from the laboratory of Dr. Juan Botas, principal investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and professor at Baylor College of Medicine, revealed that the brain downregulates glial genes involved in synaptic assembly and maintenance to protect itself from Huntington’s disease (HD). The study, which appeared in eLife Journal, highlights the critical and often overlooked roles played by glial cells in protecting from neuronal loss under neurodegenerative conditions.

When a neuron dies as a result of injury or disease, the extensive communication network between it and its neighboring cells are lost. The brain compensates for this loss of network connections by re-routing the flow of information through other nodes in the network. Typically, in neurodegenerative conditions such as Huntington’s, Alzheimer’s or Parkinson’s diseases, so many neurons are lost that eventually this compensatory re-routing becomes impossible. So far, most research on neurodegenerative diseases has focused on neurons. However, it is becoming increasingly apparent that glial cells, which were initially thought to be involved only in housekeeping functions, play significantly more important and direct roles in the formation and maintenance of synaptic connections.  

To investigate the role of glia cells in the pathogenesis of Huntington’s disease, the team studied alterations in the gene expression patterns of fruit flies expressing human mutant Huntingtin (mHTT) in either glia and/or neurons. Further, they compared these changes in gene expression patterns to those observed in the brains of HD patients and mice. 

“We previously studied a Drosophila model of Huntington’s disease expressing human mutant Huntingtin (mHTT) in neurons to understand which of the many gene expression changes that occur in HD are pathogenic and which ones are compensatory. One class of compensatory changes affected genes involved in synaptic function. We were then curious to understand the role of glial cells in synapse gene expression changes and whether they contributed to compensatory mechanisms. This led us to the current study, for which we first generated flies that express mHTT only in glia, only in neurons, or in both cell types and then compared transcriptomic changes observed in the brains of human HD subjects, HD mouse and fruit fly models,” said Botas, who is also the director of the High-Throughput Behavioral Screening Core at the Duncan NRI. 

They then manipulated each candidate gene in fruit fly model system to assess when the observed alterations in gene expression would relieve or aggravate nervous system dysfunction. The health of the nervous system was measured using a high-throughput robotic system that assesses locomotor behavior quantitatively. They found that in HD flies, the brain downregulates glial genes that are involved in synaptic assembly and maintenance, and that this downregulation is protective.   

“Our study shows, in fact, that expression of mHTT solely in glia is sufficient to drive disease pathogenesis and highlights the need to include glia in the analysis of pathogenic mechanisms of neurological diseases. Moreover, it also demonstrates how some molecular alterations might in fact be beneficial. For instance, many of the expression profile changes we observed in mHTT neurons were compensatory or protective and not pathogenic. Making this determination is critical, because using a drug that antagonizes/reduces all disease-associated alterations may not be a wise therapeutic approach. A nuanced and targeted approach would have a greater chance of success,” Botas concluded. 

---------------------------------------------------------------------------------------------------------------------

Other researchers involved in the study were Tarik Seref OnurAndrew LaitmanHe ZhaoRyan KeyhoHyemin KimJennifer WangMegan MairHuilan Wang , Lifang Li , Alma Perez , Maria de Haro , Ying-Wooi Wan , Genevera Allen , Boxun Lu , Ismael Al-Ramahi  and Zhandong Liu . They are affiliated with one or more of the following institutions: Texas Children’s Hospital, Baylor College of Medicine, Fudan University, and Rice University. The study was supported by grants from the National Institutes of Health, CHDI, Natural Science Foundation of China, NIGMS Ruth L. Kirschstein National Research Service Award (NRSA) Predoctoral Institutional Research Training Grant, the Baylor College of Medicine Medical Scientist Training Program, the National Library of Medicine Training Program in Biomedical Informatics and Data Science, and philanthropic donations from the Hildebrand Foundation. 

Friday, May 28, 2021