Insights into the human brain proteome: Disclosing the biological meaning of protein networks in cerebrospinal fluid

Abstract

Cerebrospinal fluid (CSF) is an excellent source of biological information regarding the nervous system, once it is in close contact and accurately reflects alterations in this system. Several studies have analyzed differential protein profiles of CSF samples between healthy and diseased human subjects. However, the pathophysiological mechanisms and how CSF proteins relate to diseases are still poorly known. By applying bioinformatics tools, we attempted to provide new insights on the biological and functional meaning of proteomics data envisioning the identification of putative disease biomarkers. Bioinformatics analysis of data retrieved from 99 mass spectrometry (MS)-based studies on CSF profiling highlighted 1985 differentially expressed proteins across 49 diseases. A large percentage of the modulated proteins originate from exosome vesicles, and the majority are involved in either neuronal cell growth, development, maturation, migration, or neurotransmitter-mediated cellular communication. Nevertheless, some diseases present a unique CSF proteome profile, which were critically analyzed in the present study. For instance, 48 proteins were found exclusively upregulated in the CSF of patients with Alzheimer's disease and are mainly involved in steroid esterification and protein activation cascade processes. A higher number of exclusively upregulated proteins were found in the CSF of patients with multiple sclerosis (76 proteins) and with bacterial meningitis (70 proteins). Whereas in multiple sclerosis, these proteins are mostly involved in the regulation of RNA metabolism and apoptosis, in bacterial meningitis the exclusively upregulated proteins participate in inflammation and antibacterial humoral response, reflecting disease pathogenesis. The exploration of the contribution of exclusively upregulated proteins to disease pathogenesis will certainly help to envision potential biomarkers in the CSF for the clinical management of nervous system diseases.

A comprehensive systematic review of CSF proteins and peptides that define Alzheimer’s disease

“…They reported 5 CSF core biomarkers associated with AD [11]. Subsequently, Bastos et al compiled data from 18 proteomic studies to obtain 309 proteins expressed differentially in CSF obtained from AD patients vs. controls [12]. The most recent CSF proteomic analysis, which appeared while we were finishing our study, included 29 studies, of which 25 specifically investigated differences between AD and controls, and reported that 478 proteins exhibited different levels in AD compared to controls [13].…”

Proteomic signatures of neuroinflammation in Alzheimer’s disease, multiple sclerosis and ischemic stroke

“…Although CSF has insignificant amounts of plasma proteins compared to blood, the albumin concentration is still nine-fold higher than the lowest abundant protein [36]. Furthermore, CSF is cleared of metabolites up to four times daily [37], so changes occurring sporadically or episodically may not impact the CSF protein profile [38]. Several CSF proteomes have been published, where most have used antibody-depletion of high abundant proteins (albumin and immunoglobulin), twodimensional gel separation, and then mass spectrometry resulting in the identification of hundreds of proteins [36].…”

Digging Deep into Peptidomics Applied to Body Fluids

“…CSF is an excellent source of biological information regarding the nervous system homeostasis . Neuropeptides are known to mediate the communication between cells of the nervous system.…”

“…According to the cluster analysis performed with Cytoscape in ClueGo+CluePedia plugin, the most representative biological processes were “protein activation cascade”, “blood coagulation”, “complement activation”, “regulation of axogenesis”, and “macromolecular complex remodeling”. Changes in most of these biological processes have been reported in several diseases of central nervous system such as Alzheimer disease and multiple sclerosis (reviewed by ). Despite being less susceptible to systemic circulating protein levels, 19 precursor proteins identified in CSF were also reported in serum and 21 in saliva.…”