Expression of TAU in insulin-secreting cells and its interaction with the calcium-binding protein secretagogin

Abstract

Tauopathies have been associated with Alzheimer's disease (AD), which frequently manifests together with diabetes mellitus type 2. Calcium-binding proteins such as the recently identified secretagogin (SCGN) might exert protective effects. As pancreatic b-cells and neurons share common electrophysiological properties, we investigated the appearance of TAU (listed as MAPT in the HUGO and MGI Databases) protein at the islets of Langerhans and b-cellderived cell lines which highly express the neuroendocrinespecific protein SCGN. Six predominant TAU isoforms could be identified by immunoblotting, which formed TAU deposits detectable by immunofluorescence and sarkosylinsoluble pellets. Using GST-SCGN pull-down assays, a calcium-dependent SCGN-TAU interaction was found. In this line, sucrose density gradient fractionation and differential ultracentrifugation studies of TAU and SCGN revealed co-appearance of both proteins. Co-localization of TAU and SCGN within insulinoma cells and islets of Langerhans mainly restricted to insulin-positive b-cells was demonstrated by confocal microscopy. Motivated by these findings, we looked if SCGN overexpression could exert protective function on Rin-5F cells, which showed differences in TAU levels. Testing the vulnerability of Rin-5F clones by MTT assay, we revealed that high TAU levels going along with highest TAU aggregates could not be antagonized by high levels of SCGN protein. Our findings demonstrated for the first time the association of TAU and the calcium-binding protein SCGN and support earlier results implicating that b-cells might represent an extra cerebral site of tauopathy.

Distribution patterns of calcium-binding proteins in pancreatic tissue of non-diabetic as well as type 2 diabetic rats and in rat insulinoma β-cells (INS-1)

“…Our SCGN labeling demonstrates strong distribution in the cerebellum and in the pituitary gland, as was also described by Gartner et al (2001). SCGN labeling of pancreatic islets and INS-1 cells seen here was consistent with the recent report by Maj et al (2010). The speciWcity of primary antibodies against CaBPs, which were used for immunohistochemistry, was proven by western blotting.…”

Expression of secretagogin in clear-cell renal cell carcinomas is associated with a high metastasis rate

“…This might influence the expression intensity of numerous other proteins potentially important for tumor biology. Most interestingly, recent data demonstrate a cell-protective potential of SCGN and other calcium-binding proteins in neurons of the central nervous system [36,37]. This might be of similar relevance for CCRCC cells, thus favoring metastasis.…”

Calcium Binding and Disulfide Bonds Regulate the Stability of Secretagogin towards Thermal and Urea Denaturation

“…Secretagogin has a distinct set of ten known targets that are mostly vesicular proteins, but also some cytosolic enzymes [9, 14–18]. The reported targets are SNAP25 involved in Ca 2+ -induced exocytosis [9], SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, β-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2 [14] as well as the 4R isoform of Tau [18].…”

“…The reported targets are SNAP25 involved in Ca 2+ -induced exocytosis [9], SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, β-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2 [14] as well as the 4R isoform of Tau [18]. Secretagogin function as a Ca 2+ sensor has been investigated in a range of physiological processes.…”

“…Secretagogin function as a Ca 2+ sensor has been investigated in a range of physiological processes. Studies of secretagogin function in insulin synthesis and secretion [10] have revealed an increase in expression of secretagogin in pancreatic β-cells in response to insulin [18]. Most recently, a putative role for secretagogin in the release of corticotrophin-releasing hormone by parvocellular neurons of the hypothalamic paraventricular nucleus in stress responsiveness has been described [19].…”