The CLDN5 gene at the blood-brain barrier in health and disease.
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| Abstract |
The CLDN5 gene encodes claudin-5 (CLDN-5) that is expressed in endothelial cells and forms tight junctions which limit the passive diffusions of ions and solutes. The blood-brain barrier (BBB), composed of brain microvascular endothelial cells and associated pericytes and end-feet of astrocytes, is a physical and biological barrier to maintain the brain microenvironment. The expression of CLDN-5 is tightly regulated in the BBB by other junctional proteins in endothelial cells and by supports from pericytes and astrocytes. The most recent literature clearly shows a compromised BBB with a decline in CLDN-5 expression increasing the risks of developing neuropsychiatric disorders, epilepsy, brain calcification and dementia. The purpose of this review is to summarize the known diseases associated with CLDN-5 expression and function. In the first part of this review, we highlight the recent understanding of how other junctional proteins as well as pericytes and astrocytes maintain CLDN-5 expression in brain endothelial cells. We detail some drugs that can enhance these supports and are being developed or currently in use to treat diseases associated with CLDN-5 decline. We then summarise mutagenesis-based studies which have facilitated a better understanding of the physiological role of the CLDN-5 protein at the BBB and have demonstrated the functional consequences of a recently identified pathogenic CLDN-5 missense mutation from patients with alternating hemiplegia of childhood. This mutation is the first gain-of-function mutation identified in the CLDN gene family with all others representing loss-of-function mutations resulting in mis-localization of CLDN protein and/or attenuated barrier function. Finally, we summarize recent reports about the dosage-dependent effect of CLDN-5 expression on the development of neurological diseases in mice and discuss what cellular supports for CLDN-5 regulation are compromised in the BBB in human diseases.
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| Authors | Yosuke Hashimoto, Chris Greene, Arnold Munnich, Matthew Campbell |
| Journal | Fluids and barriers of the CNS (Fluids Barriers CNS) Vol. 20 Issue 1 Pg. 22 (Mar 28 2023) ISSN: 2045-8118 [Electronic] England |
| PMID | 36978081 (Publication Type: Journal Article, Review) |
| Copyright | © 2023. The Author(s). |
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