Hong Kong scientists uncover key protein in strengthening cerebrospinal fluid barrier
A team of researchers at the Chinese University of Hong Kong (CUHK), led by Associate Professor Kwan Kin-ming (Croucher Scholarship 1991), has solved a mystery concerning the human brain and spinal cord that lays the groundwork for developing novel therapeutic strategies for preventing and treating neurodevelopmental disorders, including some COVID-19 complications.
Our brain and spinal cord are surrounded by cerebrospinal fluid (CSF), a clear, colourless fluid that is produced by a complex network of blood vessels named choroid plexus. The region consists of modified ependymal cells and a core of capillaries and connective tissue that filters blood and restricts harmful molecules from entering into the central nervous system.
Together they form a blood-CSF barrier that protects the nervous system and the brain.
Impairment of the choroid plexus is known to be related to various neurodevelopmental disorders such as autism and Alzheimer’s disease. In addition, it can lead to an abnormal build-up of CSF in the brain ventricles of new-borns, affecting one in 1,000 babies.
More recently, it has been found that neurological complications in COVID-19 patients are also a result of infection at the choroid plexus, which damages the epithelial blood-CSF barrier. However, how this barrier function is regulated at the choroid plexus was previously unknown.
Kwan’s team, working in collaboration with Professor Jiang Liwen (Croucher Senior Research Fellowship 2015 and 2009) and other CUHK academics, has now uncovered the mechanisms behind the permeability of the barrier.
The research was published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), a leading scientific journal.
The CUHK researchers found that a transcription factor – SOX9 protein – is an essential regulatory factor of the choroid plexus, ensuring the correct composition of CSF.
In earlier research, they had observed that when the SOX9 protein is missing, the hyperpermeability of the blood-CSF barrier increases. In the recently published study, they found that when the protein was not present in mice, fluorescent tracers could enter brain tissue by passing through the choroid plexus into the CSF.
There was a dramatic increase in the CSF protein level with an abnormal deposition of blood-borne proteins in the CSF of mutant mice, a common phenomenon seen in patients with hydrocephalus. Such a change in CSF composition significantly affected proper brain development in mice.
Through RNA sequencing, the team also found that SOX9 is required for the synthesis of collagen IX at the choroid plexus epithelium. Using a temporal in utero gene knockdown approach, the team demonstrated that mice lacking collagen IX showed characteristics that closely resembled those of blood-CSF barrier impairment in SOX9 mutants.
Deficiency of collagen IX markedly increased the vulnerability of the basement membrane and perturbed the dynamics required for the maintenance of epithelial apicobasal polarity as well as the tight junction structures.
These tight junctions, found between adjacent epithelial cells, are critical for restricting unauthorised passage of molecules across the choroid plexus.
To understand how to prevent breaching of the barrier, or how to repair the permeable barrier, Kwan said it was necessary to find out more about the regulatory mechanisms behind the function of the blood-CSF barrier.
“Therapeutic strategies that aim at intervening in the function of blood-CSF barrier or modifying CSF constituents represent promising approaches to treating neurodevelopmental and neurological disorders,” he explained.
Kwan said that the CUHK researchers are now attempting to harness the choroid plexus function to alleviate CSF-related neurological disorders.
Kwan Kin-ming is Associate Dean (Education), Associate Professor, and Director of the Natural Sciences Programme in the Faculty of Science at the Chinese University of Hong Kong (CUHK). He undertook undergraduate and doctoral studies at the University of Hong Kong, and postdoctoral research at the University of Texas MD Anderson Cancer Center in the US. He received his Croucher Scholarship in 1991.
To view Kwan’s Croucher profile, please click here.
Jiang Liwen is Professor in the School of Life Sciences and Director of several research centres at the Chinese University of Hong Kong, including the Centre for Cell & Developmental Biology. He received a BSc from South China Agricultural University in 1984. In Canada, he earned a Master of Science at the University of British Columbia in 1992 and a PhD at Simon Fraser University, in 1996. Jiang has received two Croucher Senior Research Fellowships, in 2015 and 2009 respectively.
To view Professor Jiang’s Croucher profile, please click here.