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Cerebrospinal Fluid Signature of Hydrocephalus


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The Mpdz KO mouse model characterized by my lab (Yang et al., EMBO Mol Med, 2019) phenocopies congenital hydrocephalus in patients harboring loss-of-function mutations in the human homologue, MPDZ. Though congenital hydrocephalus is frequently an inherited condition, only nine genes had been genetically linked to it. Despite the low frequency of hydrocephalus linked to MPDZ (1:2300), its pathophysiological mechanism is likely to be shared by hydrocephali linked to other genes because MPDZ-linked hydrocephalus is caused by hyperpermeability of the choroid plexus (CP), the major source of the cerebrospinal fluid (CSF). The main defects we identified and quantified in the Mpdz KO mouse occur in the epithelial cell monolayer that forms the wall of the CP villi. Both the paracellular and transcellular permeabilities of this monolayer were significantly higher than in their wild type (WT) counterparts. To determine if the defects in CP epithelial cells altered the composition of the CSF, we undertook comparative proteomics of the sera and CSF of WT and Mpdz KO mice. We found no significant differences between the serum protein compositions, indicating that the alteration in the composition of the CSF originated in the CP. In contrast, the total protein concentration was more than 2.5-fold higher in the CSF of the Mpdz KO mice. A total of 23 proteins were at least 2-fold over-abundant in the CSF of the latter. Ontologically, these proteins can be classified into 7 distinct group: extracellular matrix, coagulation cascade, lipoproteins, immune system, cytokine-binding proteins (to insulin-like growth factor, IGF), and blood pressure regulation (angiotensinogen). Most of these groups have known roles in the response of the brain to stress: extracellular matrix proteins and lipoprotein secretion increases in response to injury; coagulation cascade protein abundance increases in neuroinflammation; the secretion of IGF-binding proteins would inhibit brain growth as a negative feedback to the expansion caused by the swelling ventricles; angiotensinogen, an angiotensin precursor, would be secreted to increase blood pressure and maintain blood flow against the intracranial pressure. Rather than a haphazard group, the over-abundance of these proteins is a likely concerted response to hydrocephalus and may be regarded as signature of this condition.


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