Inference of Diagnostic Markers and Therapeutic Targets from CSF proteomics for the Treatment of Hydrocephalus

Abstract

We hypothesize that the composition of the CSF provides specific information on damage sustained by the hydrocephalus-harboring brain and on its autoregulatory responses to the intracranial pressure (ICP) exerted on the parenchyma. The data analyzed to form this hypothesis was generated in a previous study by comparative proteomics of CSF collected from the brain of healthy and Mpdz knockout (KO) mice 1 . These mice phenocopy the severe hydrocephalus linked to human loss-offunction mutants of the same gene 2, 3 . The overall protein concentration was 2.5-fold higher in the CSF of Mpdz KO versus healthy mice. Practically all the 313 proteins identified by mass spectroscopy were overabundant in the CSF of the KO mice. Proteins that were more than 2-fold overabundant in the CSF of hydrocephalic mice were classified into seven functional groups. The overabundance of extracellular matrix (ECM) proteins, complement factors, and apolipoproteins indicated that the hydrocephalic brain underwent ischemia, inflammation, and demyelination. The overabundance of cytokine-binding proteins was linked uniquely to the activation of insulin-like growth factor (IGF) signaling. The overabundance of angiotensinogen and pigment epithelium-derived factor (PEDF) indicated the activity of negativefeedback mechanisms to reduce CSF production by the choroid plexus. These observations raise intriguing propositions: the composition of the CSF could be used as biomarker of case-specific injuries of ventriculomegaly in fetuses or neonates; once the overabundance of these biomarkers is detected, the IGF and angiotensin signaling pathways could be exploited to reduce CSF production as a noninvasive therapy, replacing or aiding current invasive treatments of hydrocephalus.