Astrocyte Pathophysiology In Huntington’S Disease: Characterization Of Spatial Distribution, Organization, And Function Of Distinct Populations Of Astrocytes
2024-04
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Astrocyte Pathophysiology In Huntington’S Disease: Characterization Of Spatial Distribution, Organization, And Function Of Distinct Populations Of Astrocytes
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2024-04
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Huntington’s disease (HD) is a devastating neurodegenerative disease that manifests as motor, cognitive, and psychiatric impairments. HD is caused by a poly-glutamine expansion in exon 1 of the huntingtin (HTT) gene, which results in misfolding and aggregation of the mutant HTT protein (mHTT). HD preferentially affects medium spiny neurons of the striatum, causing a severe and progressive loss of striatal cells, while other areas of the brain, such as the cortex, are affected to a lesser degree. Interestingly, degeneration of neurons in the striatum is accompanied by striatal astrogliosis and astrocytic dysfunction. However, the mechanisms by which mHTT induces striatal astrocyte pathology and its association with neuronal degeneration and behavioral deficits in HD is still unclear. This gap in knowledge has hindered the development of effective therapies to ameliorate disease progression. Here, we sought to characterize how HD affects astrocyte abundance, diversity, and distribution within the striatum using the zQ175 mouse model of HD. We focused on three types of astrocytes characterized by the expression of specific protein markers, GS+, S100B+, and GFAP+. We found that S100B+ astrocytes and GFAP+ astrocytes were more abundant in the striatum of zQ175 mice compared to WT. However, while S100B+ astrocytes were increased throughout different striatal domains, GFAP+ astrocytes were only increased in the most dorsomedial region. Additionally, we found that GFAP+ astrocytes appeared in clusters whereas S100B+ astrocytes were more homogenously distributed. Spatial clustering of astrocytes has been reported in other neurodegenerative diseases and can indicate areas of cell death, inflammation, or aggregation of toxic proteins. We found that the spatial distribution of GFAP+ astrocytes in zQ175 mice surprisingly reflected areas of low HTT aggregate load and corresponded to white matter fascicles passing through the striatum. Intriguingly, we also found that GFAP+ astrocytes only accumulated around a specific subset of fascicles in the dorsomedial striatum. To determine the origin of those fascicles, we utilized the Allen Mouse Brain Connectivity Atlas and conducted viral tracing experiments. We determined that the secondary motor area (MOs), a cortical region involved in motor actions and decision making, sends fascicles through the dorsomedial region of the striatum. We then confirmed that GFAP+ astrocytes are specifically associated with fascicles originating in the MOs and looked for pathology in the MOs as a reason for this interaction. We saw a significant increase in GFAP+ astrocytes in the MOs of zQ175 mice compared to WT. Taken together, this research demonstrates that HD differentially affects the abundance and distribution of distinct types of astrocytes in the striatum. This information is vital to understanding the contribution of astrocytes to HD pathology. In fact, we show that an increase in number of S100B+ astrocytes in the striatum likely reflects the response of protoplasmic astrocytes to striatal gray matter pathology. In contrast, an increase in number of GFAP+ astrocytes in the striatum is probably a response to pathology of cortical neurons or white matter. Astrocyte heterogeneity and the MOs are two understudied areas of research in HD and our work emphasizes the importance of further research into these topics with the hope of uncovering the distinct roles of each in disease pathogenesis.
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University of Minnesota Ph.D. dissertation. April 2024. Major: Neuroscience. Advisor: Rocio Gomez-Pastor. 1 computer file (PDF); ix, 134 pages.
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