The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular functions and those which mainly exert extracellular regulatory effects. S100 proteins are only expressed in vertebrates and show cell-specific expression patterns. In some instances, a particular S100 protein can be induced in pathological circumstances in a cell type that does not express it in normal physiological conditions. Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors and nucleic acids. Some S100 proteins are secreted or released and regulate cell functions in an autocrine and paracrine manner via activation of surface receptors (e.g. the receptor for advanced glycation end-products and toll-like receptor 4), G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans. Extracellular S100A4 and S100B also interact with epidermal growth factor and basic fibroblast growth factor, respectively, thereby enhancing the activity of the corresponding receptors. Thus, extracellular S100 proteins exert regulatory activities on monocytes/macrophages/microglia, neutrophils, lymphocytes, mast cells, articular chondrocytes, endothelial and vascular smooth muscle cells, neurons, astrocytes, Schwann cells, epithelial cells, myoblasts and cardiomyocytes, thereby participating in innate and adaptive immune responses, cell migration and chemotaxis, tissue development and repair, and leukocyte and tumor cell invasion.

Functions of S100 Proteins

S100 proteins regulate intracellular processes such as cell growth and motility, cell cycle regulation, transcription and differentiation. Twenty members have been identified so far, and altogether, S100 proteins represent the largest subgroup in the EF-hand Ca2+ -binding protein family. A unique feature of these proteins is that individual members are localized in specific cellular compartments from which some are able to relocate upon Ca2+ activation, transducing the Ca2+ signal in a temporal and spacial manner by interacting with different targets specific for each S100 protein. Some members are even secreted from cells exerting extracellular, cytokine-like activities partially via the surface receptor RAGE (receptor for advanced glycation endproducts) with paracrine effects e.g. on neurons, promoting their survival during development or after injury. Another important aspect is that 14 bona fide S100 genes are found in a gene cluster on human chromosome 1q21 where a number of chromosomal abnormalities occur. This results in a deregulated expression of some S100 genes associated with neoplasias. Recently, S100 proteins have received increasing attention due to their close association with several human diseases including cardiomyopathy, neurodegenerative disorders and cancer. They have also been proven to be valuable in the diagnostic of these diseases, as predictive markers of improving clinical management, outcome and survival of patients and are considered having a potential as drug targets to improve therapies.

S100 proteins: structure, functions and pathology.

S100B's double life: Intracellular regulator and extracellular signal

Background: MicroRNAs (miRNAs) are endogenous, small noncoding RNAs. Because of their size, abundance, tissue specificity, and relative stability in plasma, miRNAs hold promise as unique accessible biomarkers to monitor tissue injury. Methods: We investigated the use of liver-, muscle- and brain-specific miRNAs as circulating biomarkers of tissue injury. We used a highly sensitive quantitative PCR assay to measure specific miRNAs (miR-122, miR-133a, and miR-124) in plasma samples from rats treated with liver or muscle toxicants and from a rat surgical model of stroke. Results: We observed increases in plasma concentrations of miR-122, miR-133a, and miR-124 corresponding to injuries in liver, muscle, and brain, respectively. miR-122 and miR-133a illustrated specificity for liver and muscle toxicity, respectively, because they were not detectable in the plasma of animals with toxicity to the other organ. This result contrasted with the results for alanine aminotransferase (ALT) and aspartate aminotransferase, which were both increased with either organ toxicity. Furthermore, miR-122 exhibited a diagnostic sensitivity superior to that of ALT when the results were correlated to the liver histopathologic results. The miR-124 concentration increased in the plasma of rats 8 h after surgery to produce brain injury and peaked at 24 h, while the miR-122 and miR-133a concentrations remained at baseline values. Conclusions: These results demonstrate that tissue-specific miRNAs may serve as diagnostically sensitive plasma biomarkers of tissue injury.

/pdf/plasma-micrornas-as-sensitive-and-specific-biomarkers-of-50zcyy76so.pdf

Plasma MicroRNAs as Sensitive and Specific Biomarkers of Tissue Injury

S100B is a calcium-binding peptide produced mainly by astrocytes that exert paracrine and autocrine effects on neurons and glia. Some knowledge has been acquired from in vitro and in vivo animal experiments to understand S100B's roles in cellular energy metabolism, cytoskeleton modification, cell proliferation, and differentiation. Also, insights have been gained regarding the interaction between S100B and the cerebral immune system, and the regulation of S100B activity through serotonergic transmission. Secreted glial S100B exerts trophic or toxic effects depending on its concentration. At nanomolar concentrations, S100B stimulates neurite outgrowth and enhances survival of neurons during development. In contrast, micromolar levels of extracellular S100B in vitro stimulate the expression of proinflammatory cytokines and induce apoptosis. In animal studies, changes in the cerebral concentration of S100B cause behavioral disturbances and cognitive deficits. In humans, increased S100B has been detected with various clinical conditions. Brain trauma and ischemia is associated with increased S100B concentrations, probably due to the destruction of astrocytes. In neurodegenerative, inflammatory and psychiatric diseases, increased S100B levels may be caused by secreted S100B or release from damaged astrocytes. This review summarizes published findings on S100B regarding human brain damage and neurodegeneration. Findings from in vitro and in vivo animal experiments relevant for human neurodegenerative diseases and brain damage are reviewed together with the results of studies on traumatic, ischemic, and inflammatory brain damage as well as neurodegenerative and psychiatric disorders. Methodological problems are discussed and perspectives for future research are outlined.

S100B in brain damage and neurodegeneration

1 Roy A. Psychiatr Q 1993; 64: 345–358. 2 Mann JJ In: Bloom FE and Kupfer DJ(eds). Psychopharmacology: The Fourth Generation of Progress. Raven Press: New York, 1995; 1919–1928. 3 Asberg M, Traskman L, Thoren P. Arch Gen Psychiatry 1976; 33: 1193–1197. 4 Nordstrom P, Samuelsson M, Asberg M, Traskman-Bendz L, AbergWistedt A, Nordin C et al. Suicide Life Threat Behav 1994; 24: 1–9. 5 Fitzpatrick PF. Annu Rev Biochem 1999; 68: 355. 6 Rujescu D, Giegling I, Sato T, Hartmann AM, Moller HJ. Biol Psychiatry 2003; 54: 465–473. 7 Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H et al. Science 2003; 299: 76. 8 Ono H, Shirakawa O, Kitamura N, Hashimoto T, Nishiguchi N, Nishimura A et al. Mol Psychiatry 2002; 7: 1127–1132. 9 McGuffin P, Katz R. Br J Psychiatry 1989; 155: 294–304. 10 Owens MJ, Nemeroff CB. Clin Chem 1994; 40: 288–295. 11 Nielsen DA, Goldman D, Virkkunen M, Tokola R, Rawlings R, Linnoila M. Arch Gen Psychiatry 1994; 51: 34–38. 12 Mann JJ, Malone KM, Nielsen DA, Goldman D, Erdos J, Gelernter J. Am J Psychiatry 1997; 154: 1451–1453. 13 Du L, Bakish D, Hrdina PD. J Affect Disord 2001; 65: 37–44.

Glial cell dysfunction in schizophrenia indicated by increased S100B in the CSF.

S100B, a calcium-binding protein produced by astroglial cells, is a marker of astroglial cellular integrity. It has been shown to be increased in acute brain damage and neurodegeneration. A recent study showed increased S100B levels in medicated acutely psychotic patients with schizophrenia. The study presented here included 26 drug-free patients with acute schizophrenia and 26 matched healthy controls. S100B blood concentrations were determined using a quantitative immunoassay upon admission and after 6 weeks of neuroleptic treatment. The PANSS was used to investigate psychopathology. Unmedicated schizophrenic patients showed significantly increased S100B levels compared to matched healthy controls. After 6 weeks of treatment, 11 patients showed normal S100B levels while in 15 patients the levels remained increased. These patients showed significantly higher PANSS negative scores upon admission and after 6 weeks of treatment. Schizophrenic patients display a loss of astroglial integrity which is not caused by neuroleptic medication. Continuously increased S100B levels are associated with negative symptomatology.

Matthias Rothermundt

Papers

S100B in brain damage and neurodegeneration

Glial cell dysfunction in schizophrenia indicated by increased S100B in the CSF.

Increased S100B blood levels in unmedicated and treated schizophrenic patients are correlated with negative symptomatology

S100B and response to treatment in major depression: a pilot study.

Elevated plasma levels of S-100b protein in schizophrenic patients.