The role of astrocytes in human Huntington's disease pathology

Huntington's disease (HD) is a neurodegenerative disorder caused by a repeat expansion in the HTT gene. The disease is well known for severe and progressive loss of neurons in the caudate and putamen, although other areas are also involved. Much of the attention on understanding the mechanisms underlying HD has focused on the neurons. The brain also contains large numbers of glial cells, such as astrocytes, oligodendrocytes, and microglia, which also become dysfunctional in HD. Astrocytes are one of the most abundant cell types in the central nervous system and are critical for regulating the brain environment and supporting neurons in many ways. In this review, we discuss the changes in astrocytes during the evolution of HD in the human brain. We detail the key phenotypes of astrocytes in human HD, which encompass reactive astrogliosis, loss of homeostatic function, gain of a neuroprotective function, changes in lipid metabolism, huntingtin protein aggregation, and limited somatic repeat expansion. We briefly discuss the conservation of these phenotypes in mouse models and propose a model of how astrocyte states change in human HD. Finally, we present open questions for astrocyte researchers in the HD field. Together, this review represents a valuable resource for readers interested in astrocytic changes in human HD.