Contribution of Glial Cells to Polyglutamine Diseases: Observations from Patients and Mouse Models

Neurodegenerative diseases are broadly characterized neuropathologically by the degeneration of vulnerable neuronal cell types in a specific brain region. The degeneration of specific cell types has informed on the various phenotypes/clinical presentations in someone suffering from these diseases. Prominent neurodegeneration of specific neurons is seen in polyglutamine expansion diseases including Huntington's disease (HD) and spinocerebellar ataxias (SCA). The clinical manifestations observed in these diseases could be as varied as the abnormalities in motor function observed in those who have Huntington's disease (HD) as demonstrated by a chorea with substantial degeneration of striatal medium spiny neurons (MSNs) or those with various forms of spinocerebellar ataxia (SCA) with an ataxic motor presentation primarily due to degeneration of cerebellar Purkinje cells. Due to the very significant nature of the degeneration of MSNs in HD and Purkinje cells in SCAs, much of the research has centered around understanding the cell autonomous mechanisms dysregulated in these neuronal cell types. However, an increasing number of studies have revealed that dysfunction in non-neuronal glial cell types contributes to the pathogenesis of these diseases. Here we explore these non-neuronal glial cell types with a focus on how each may contribute to the pathogenesis of HD and SCA and the tools used to evaluate glial cells in the context of these diseases. Understanding the regulation of supportive and harmful phenotypes of glia in disease could lead to development of novel glia-focused neurotherapeutics.

Automated summary

Neurodegenerative diseases are characterized by the degeneration of specific neuronal cell types in the brain, leading to various clinical presentations. In diseases like Huntington's disease (HD) and spinocerebellar ataxias (SCA), the degeneration of specific neurons, such as striatal medium spiny neurons (MSNs) in HD or cerebellar Purkinje cells in SCA, contributes to the observed abnormalities in motor function. While research has primarily focused on understanding dysregulated mechanisms in these neuronal cell types, recent studies suggest that dysfunction in non-neuronal glial cell types also contributes to disease pathogenesis. This article explores the role of glial cells in HD and SCA and the potential for developing glia-focused neurotherapeutics.