The contribution of glial cells to Huntington's disease pathogenesis

Abstract

Glial cells play critical roles in the normal development and function of neural circuits, but in many neurodegenerative diseases, they become dysregulated and may contribute to the development of brain pathology. In Huntington's disease (HD), glial cells both lose normal functions and gain neuropathic phenotypes. In addition, cell-autonomous dysfunction elicited by mutant huntingtin (mHTT) expression in specific glial cell types is sufficient to induce both pathology and Huntington's disease–related impairments in motor and cognitive performance, suggesting that these cells may drive the development of certain aspects of Huntington's disease pathogenesis. In support of this imaging studies in pre-symptomatic HD patients and work on mouse models have suggested that glial cell dysfunction occurs at a very early stage of the disease, prior to the onset of motor and cognitive deficits. Furthermore, selectively ablating mHTT from specific glial cells or correcting for HD-induced changes in their transcriptional profile rescues some HD-related phenotypes, demonstrating the potential of targeting these cells for therapeutic intervention. Here we review emerging research focused on understanding the involvement of different glial cell types in specific aspects of HD pathogenesis. This work is providing new insight into how HD impacts biological functions of glial cells in the healthy brain as well as how HD induced dysfunction in these cells might change the way they integrate into biological circuits.