Molecular mechanisms underlying cerebral small vessel disease associated with mutations in COL4A1

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Authors

Yamasaki, Evan

Issue Date

2023

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Dissertation

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Calcium signaling , Cerebral small vessel disease , Collagen , Ion channels , Myogenic tone , Neurovascular coupling

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Cerebral small vessel diseases (cSVDs) are the leading cause of stroke and vascular dementia, but the underlying pathogenic mechanisms are unknown. Humans and mice with autosomal dominant mutations in the collagen-encoding gene COL4A1 present with brain pathology that typifies cSVD. Data in this thesis reveals divergent pathogenic mechanisms in two Col4a1 mutant mouse models and offers viable therapeutic strategies for treating related cSVDs. Col4a1G1344D cSVD was associated with the loss of myogenic tone due to blunted pressure-induced smooth muscle cell (SMC) depolarization. Dysregulation of membrane potential was linked to impaired Ca2+-dependent activation of transient receptor potential melastatin 4 (TRPM4) channels caused by disruption in sarcoplasmic reticulum (SR) Ca2+ signaling. Deficits were prevented by treating mice with 4-phenylbutyrate, a compound that promotes the trafficking of misfolded proteins from the SR, suggesting accumulation of mutant collagen in the SR contributes to the pathogenesis. The fundamental defect in Col4a1G394V cSVD was the depletion of phosphatidylinositol 4,5 bisphosphate (PIP2), a necessary cofactor for TRPM4 and inwardly-rectifying K+ (KIR) channels, in vascular SMCs and endothelial cells. This caused a loss of myogenic tone and neurovascular coupling contributing to cSVD. PIP2 depletion was linked to increased phosphoinositide 3-kinase (PI3K) activity acting downstream of transforming growth factor-beta (TGF-β) receptors. Restoring PIP2 by blocking PI3K or TGF-β receptors restored myogenic tone, neurovascular coupling, and memory function. Differences in pathogenic mechanisms between mutations within the same gene highlight the diverse causes and the need for specific treatments of cSVDs.

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Creative Commons Attribution 4.0 United States

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