The proteins secreted in brain
There are 65 proteins that are predicted to be locally secreted in brain based on the manual literature analysis and data analysis. A majority of the proteins identified are brain extracellular matrix (ECM) proteins and signaling/neuropeptide molecules.
The brain ECM is composed by hyaluronic acids, glycoproteins and proteoglycans. The ECM serves as a scaffold for the construction of the tissue, and is important for cell growth regulation, differentiation, migration, adhesion and tissue morphogenesis. The brain ECM also works as a substrate for cells in regulating their motility and shape. The proteoglycans, especially the chondroitin sulfate proteoglycans and heparan sulfate proteoglycans, are the main component of the brain ECM. These large proteins have the ability to bind many other proteins including chemokines, growth factors, axon guidance molecules and cell adhesion molecules. The brain proteoglycans are abundant both in the developing and adult brain.
Neuropeptides, peptide hormones and other signaling proteins enables neurons to communicate and transmit information and these molecules play a key role in modulating neuronal activity. Neuropeptide functions are crucial in order to execute the basal and advanced functions of the vertebrate central nervous system, such as perception and sensory functions. Other proteins identified as secreted in brain are for example proteins involved in synapse function, cell adhesion proteins, cytokines and developmental proteins.
Functions of proteins locally secreted in the brain
All proteins that are secreted in brain were classified according to function based on Uniprot molecular function and biological processes keywords. The annotations were prioritized in the following hierarchy: Blood coagulation, Complement pathway, Acute phase, Cytokine, Hormone, Neuropeptide, Growth factor, Receptor, Lectin, Transport, Developmental protein, Defence, Enzyme, Enzyme inhibitor, Transcription, Immunity, Cell adhesion. Each gene was assigned one function.
The results of the analysis are presented in Figure 1. The analysis shows that 31 secreted proteins in brain lacks a distinct annotated function. However, among the remaining 34 secreted proteins, we could identify several proteins involved in development, and some proteins significant for cell adhesion, which is important for the cell-to-matrix interactions during development, axonal growth and differentiation of the brain. Many genes that gives rise to precursor neurosignaling proteins were also identified, these protein are proteolytically processed to function as biologically active neuropeptides and are vital for e.g. regulation of circadian rhythm, anorexigenic, antidiuretic, cardiovascular and sensory function.
Tissue specificity and tissue distribution classification
The genes encoding proteins locally secreted in the brain were further analyzed based on mRNA expression and categorized according to tissue specificity and tissue distribution. Almost two thirds of the genes (n=44) were classified as tissue or group enriched, i.e. having either at least five-fold higher mRNA level in one tissue or in a group of two to five tissues compared to all other tissues. A third of the genes were tissue enhanced (n=20), and only one gene was classified as not detected in any of the analyzed samples from HPA, GTEx or FANTOM (Figure 2). For most protein-coding genes, mRNA was detected either in a single tissue or in a few tissues (less than 30 percent of the analyzed tissues). A few genes (n=38) were detected in over 30 percent of the analyzed tissues (Figure 3).
Figure 2. Number of genes encoding proteins that are secreted in brain, categorized according to tissue specificity. Categories include: tissue enriched, defined as mRNA level in one tissue at least five-fold higher than all other tissues; group enriched, defined as five-fold higher average mRNA level in a group of two to five tissues all other tissues; tissue enhanced, defines as five-fold higher average mRNA level in one or more tissues compared to the mean mRNA level of all tissues; expressed in all, defined as ≥ 1 NX in all tissues; and not detected, defined as < 1 NX in all tissues.
Figure 3. Number of genes encoding proteins that are intracellular or membrane-bound, categorized according to tissue distribution. Categories include: detected in all, defined as n=100%; detected in many (defined as 31%=< n < 100%) detected in some, defined as 1< n < 31%; detected in single defined as single n=1; and not detected, n=0.
Origin of proteins locally secreted in the brain
A classification of gene expression showed that several proteins annotated as secreted in the brain are mainly produced in the brain and show a tissue-enriched expression pattern on mRNA level (Figure 4).
Secreted brain ECM proteins and cell adhesion proteins
During brain development, high levels of chondroitin sulfate proteoglycans are expressed, such as the neurocan (NCAN), versican (VCAN), and brevican proteins (BCAN), and they are also abundantly expressed in the adult brain. Both neurocan and brevican are important for neuronal cell differentiation, adhesion and neurite growth during development by binding to neural cell adhesion molecules. These proteins also stabilizes the interactions between hyaluronan molecules and brain proteoglycans. Interestingly, studies have shown that brevican is highly expressed in gliomas and could promote brain tumor cell growth and motility. The HAPLN4 gene, encoding a hyaluronan and proteoglycan linker protein, is produced by neurons and binds to hyaluronic acids and chondroitin sulfate proteoglycans.
The TNR gene encodes the tenascin R protein. Tenascins are multimeric vertebrate ECM glycoproteins that binds to other ECM glycoproteins such as fibronectin, heparin, heparan sulfate and chondroitin sulfate proteins. The expression of tenascin R protein is restricted to the central nervous system and this particular protein promotes neurite outgrowth and neural cell adhesion. The SLITRK1 gene encodes a member of the SLITRK integral membrane protein family. SLITRK1 is important for synaptogenesis, neurite growth and promotes excitatory synapse differentiation. SLITKR1 shares high sequence homology with neurotrophin receptors and studies show that mutations in this gene are associated with Tourette syndrome. Contactin 2, encoded by the CNTN2 gene, is another cell adhesion molecule, and similarly as tenascin R and SLITRK1, contactin 2 is implicated in cell migration, and axon development and proliferation.
Secreted proteins in brain implicated in neuronal signaling
The protein encoded by the PDYN gene is a preproprotein that is proteolytically cleaved to generate secreted opioid peptides called leumorphin, beta-neoendorphin, dynorphin, leu-enkephalin and rimorphin. The peptide ligands bind kappa-type opioid receptor, and thus have opioid-like effects. They seem to be involved in a number of physiologic functions, including pain perception and stress response.
Relevant links and publications