What are the molecular mechanisms of blood-brain barrier dysfunction in disease?
Caterina P Profaci1, Kaja Bajc1, Shawn H Fu1, Tony Z Zhang1, Richard Daneman1 1Neurosciences and Pharmacology Departments, University of California, San Diego
The blood-brain barrier (BBB) is a set of properties unique to the central nervous system (CNS) endothelial cells (ECs) that comprise the inner walls of blood vessels. In contrast to peripheral vessels, which allow extensive exchange of molecules and ions between the blood and tissue, CNS ECs exert tight control over what can enter the parenchyma. BBB dysfunction is a key component of many neurological conditions, including multiple sclerosis (MS), stroke, epilepsy, and traumatic brain injury (TBI). Despite the vastly different triggers of these diseases, in each case vascular permeability causes an influx of blood-borne molecules, disruption of ionic homeostasis, and an increase in immune cell extravasation. These events contribute to the dysfunction, damage, and even degeneration of neurons, ultimately worsening clinical outcomes. Identifying common molecular changes in ECs during disease could point towards a therapeutic target for reducing BBB dysfunction in wide range of neurological diseases.
To investigate the molecular changes occurring in CNS endothelial cells during disease, we isolated endothelial cells from four disease models during BBB dysfunction and performed RNA sequencing. A set of 198 genes was upregulated across multiple conditions, suggesting a common pathway for BBB dysfunction regardless of the trigger of disease. Furthermore, many of these genes are robustly expressed in more permeable peripheral endothelial cells in health. This observation lead to the hypothesis that blood-brain barrier dysfunction in disease involves an upregulation of peripheral endothelial cell genes that then drive CNS vascular permeability.
To test this hypothesis, we screened some of the genes identified in our RNA sequencing experiment and found that PDZ and LIM domain protein 1 (Pdlim1) was sufficient to reduce barrier properties in vitro. Because Pdlim1 had previously been shown to interact with -catenin in cancerous epithelial cells, I hypothesized that Pdlim1 drives BBB dysfunction in CNS endothelial cells by sequestering -catenin in the nucleus, thereby inhibiting Wnt signaling, which is known to be necessary for BBB formation and maintenance. I found that Pdlim1 is indeed sufficient to reduce Wnt signaling in vitro, and I am currently probing this hypothesis in vivo using Pdlim1 knockout and over-expressing transgenic mice. Funding: NIH R01 NS091281 National Science Foundation (NSF) Graduate Research Fellowship Program (GRFP)
Credits: None available.
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