A new study found evidence of widespread changes in glial cell populations across multiple brain regions of post-mortum brain tissue from Huntington’s disease (HD) patients, emphasizing the significance of glial dysfunction in the pathology of HD.
HD is a genetic disorder characterized by the progressive breakdown of neurons in the brain, leading to motor dysfunction, psychiatric disturbances, and cognitive decline. The disease is caused by an abnormal expansion of the CAG repeat in the huntingtin (HTT) gene, resulting in a toxic version of the huntingtin protein. While the disease is well-known for the degeneration of medium spiny neurons (MSNs) in the striatum, evidence suggests glial cells—such as astrocytes, microglia, and oligodendrocytes—also play a key role in HD pathology.
Glial cells are essential for maintaining the brain’s microenvironment, supporting neurons, and facilitating communication within the nervous system. The study, published in Acta Neuropathologica Communications, utilized single-nuclear RNA sequencing (snRNAseq) on brain tissue from HD patients to examine the transcriptomic changes in glial cells in HD across four brain regions: the caudate nucleus (a region with prominent MSN loss), frontal cortex, hippocampus, and cerebellum.
The researchers analyzed 127,205 individual nuclei from brain tissue samples of HD patients and age-matched controls, finding significant alterations in glial cell populations across all four brain regions, with both reductions and increases in certain glial subtypes. Notably, a specific type of oligodendrocyte known as Oligo Birch, which is actively involved in myelin production, was markedly depleted in HD brains. This loss is consistent with the observed reduction in white matter integrity in HD patients.
Conversely, certain glial subtypes were enriched in HD. These included a subtype of microglia, termed Mglia Violet, which exhibited signs of immune activation, and an astrocyte subtype, Astro Thyme, which was prominent in the hippocampus.
The study not only identified changes in glial cell abundance but also highlighted alterations in gene expression. A notable finding was the upregulation of the phosphodiesterase gene PDE1A in oligodendrocytes across multiple brain regions. This gene, which is involved in cyclic nucleotide metabolism, could affect cellular functions in HD, although its precise role in the disease remains to be clarified.
Another significant discovery was the widespread upregulation of molecular chaperone genes involved in protein folding across various glial subtypes. Chaperone proteins are known for their role in maintaining protein stability and preventing aggregation, which is relevant in neurodegenerative diseases where misfolded proteins, such as mutant huntingtin, accumulate. The increase in chaperone gene expression may represent an adaptive response to the toxic effects of the mutant protein, offering potential therapeutic avenues for enhancing these cellular defense mechanisms.
The findings suggest glial cells are not merely bystanders in HD but are actively involved in the disease’s progression. The changes in glial cell states and functions were observed not only in the striatum but also in other regions like the frontal cortex and hippocampus, indicating that HD affects the brain more globally than previously thought. This challenges the neuron-centric perspective and underscores the need to consider glial cells as potential therapeutic targets.
The study provides a detailed map of glial changes in HD, paving the way for further investigation into the roles of these cells in neurodegeneration. Targeting glial cell dysfunction and enhancing the protective functions of molecular chaperones could represent novel therapeutic strategies. Additionally, understanding the region-specific differences in glial alterations may help tailor treatments to address the diverse aspects of HD pathology.
