Murine MPDZ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus

• 发表在: EMBO Molecular Medicine
• Main Authors: Junning Yang, Claire Simonneau, Robert Kilker, Laura Oakley, Matthew D Byrne, Zuzana Nichtova, Ioana Stefanescu, Fnu Pardeep‐Kumar, Sushil Tripathi, Eric Londin, Pascale Saugier‐Veber, Belinda Willard, Mathew Thakur, Stephen Pickup, Hiroshi Ishikawa, Horst Schroten, Richard Smeyne, Arie Horowitz
• 格式: 文件
• 语言: 英语
• 出版: Springer Nature 2018-12-01
• 主题: cerebrospinal fluid; choroid plexus; hydrocephalus; magnetic resonance imaging; proteomics
• 在线阅读: https://doi.org/10.15252/emmm.201809540

Abstract Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ. Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast medium penetrates into the brain ventricles of mice carrying a Mpdz loss‐of‐function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53‐fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straightforward and concise explanation for the pathophysiology of Mpdz‐linked hydrocephalus.