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Published on: March 11, 2020
An altered extracellular matrix-integrin interface contributes to Huntington's disease-associated CNS dysfunction in
Sarah J Hernandez1, Ryan G Lim2, Tarik Onur3,4,5
1Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 92697, USA.
Insights
Huntington's disease (HD) involves blood-brain barrier (BBB) dysfunction due to astrocyte and brain endothelial cell issues. Targeting integrins (ITG) may offer a new therapeutic strategy for HD by stabilizing the BBB.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Astrocytes and brain endothelial cells form the blood-brain barrier (BBB), crucial for brain function.
- Dysfunction of these cells contributes to Huntington's disease (HD) pathogenesis.
- Integrins (ITG) are cell adhesion receptors critical for BBB integrity via extracellular matrix (ECM) interaction.
Purpose of the Study:
- To investigate the role of the ECM-ITG interface in astrocytes and brain endothelial cells in HD.
- To determine if ECM-ITG dysregulation contributes to BBB dysfunction in HD.
- To explore integrins as potential therapeutic targets for HD.
Main Methods:
- Utilized patient-derived induced pluripotent stem cell (iPSC) modeling of HD.
- Examined the ECM-ITG interface in human iPSC-derived astrocytes and brain microvascular endothelial cells.
- Employed an HD Drosophila model to assess the functional consequences of ITG manipulation in glia.
Main Results:
- Identified dysregulation of the ECM-ITG interface in iPSC-derived cells from HD patients.
- Demonstrated that this disruption contributes to BBB dysfunction in HD models.
- Showed that reducing ITG expression in glia ameliorated CNS dysfunction in an HD Drosophila model.
Conclusions:
- ECM-ITG dysregulation is implicated in BBB dysfunction in Huntington's disease.
- Targeting integrin signaling presents a potential therapeutic avenue for slowing HD progression.
- Further research into ITG-based therapies could offer novel strategies for treating HD.
Abstract:
Astrocytes and brain endothelial cells are components of the neurovascular unit that comprises the blood-brain barrier (BBB) and their dysfunction contributes to pathogenesis in Huntington's disease (HD). Defining the contribution of these cells to disease can inform cell-type-specific effects and uncover new disease-modifying therapeutic targets. These cells express integrin (ITG) adhesion receptors that anchor the cells to the extracellular matrix (ECM) to maintain the integrity of the BBB. We used HD patient-derived induced pluripotent stem cell (iPSC) modeling to study the ECM-ITG interface in astrocytes and brain microvascular endothelial cells and found ECM-ITG dysregulation in human iPSC-derived cells that may contribute to the dysfunction of the BBB in HD. This disruption has functional consequences since reducing ITG expression in glia in an HD Drosophila model suppressed disease-associated CNS dysfunction. Since ITGs can be targeted therapeutically and manipulating ITG signaling prevents neurodegeneration in other diseases, defining the role of ITGs in HD may provide a novel strategy of intervention to slow CNS pathophysiology to treat HD.
