A novel calcium‐binding protein is associated with tau proteins in tauopathy

Abstract

Tauopathies are a group of neurological disorders characterized by the presence of intraneuronal hyperphosphorylated and filamentous tau. Mutations in the tau gene have been found in kindred with tauopathy. The expression of the human tau mutant in transgenic mice induced neurodegeneration, indicating that tau plays a central pathological role. However, the molecular mechanism leading to tau-mediated neurodegeneration is poorly understood. To gain insights into the role that tau plays in neurodegeneration, human tau proteins were immunoprecipitated from brain lysates of the tauopathy mouse model JNPL3, which develops neurodegeneration in age-dependent manner. In the present work, a novel EF-hand domain-containing protein was found associated with tau proteins in brain lysate of 12-month-old JNPL3 mice. The association between tau proteins and the novel identified protein appears to be induced by the neurodegeneration process as these two proteins were not found associated in young JNPL3 mice. Consistently, the novel protein co-purified with the pathological sarkosyl insoluble tau in terminally ill JNPL3 mice. Calcium-binding assays demonstrated that this protein binds calcium effectively. Finally, the association between tau and the novel calcium-binding protein is conserved in human and enriched in Alzheimer's disease brain. Taken together, the identification of a novel calcium-binding protein associated with tau protein in terminally ill tauopathy mouse model and its confirmation in human brain lysate suggests that this association may play an important physiological and/or pathological role.

Swiprosin-1/EFhd2 Controls B Cell Receptor Signaling through the Assembly of the B Cell Receptor, Syk, and Phospholipase C γ2 in Membrane Rafts

“…Whereas NF-AT has not been studied so far, we showed already that Swip-1 blocks expression of the antiapoptotic NF-kB target gene bclxL (22). An explanation could be that Swip-1 binds calcium directly (27) and is therefore part of a negative feedback loop. Because Swip-1 blocks NF-kB in WEHI231 cells (22), we propose that Swip-1 rather counteracts tonic BCR survival signaling (72), despite inducing constitutive membrane raft association of Syk, PLCg2, and the mHC in WEHI231 cells.…”

“…Swip-1 targets PLCg2 and Syk to membrane rafts likely in an SLP-65-independent manner, although we cannot exclude involvement of (53), and it can possibly associate with microtubule-associated tau proteins (27). In that sense, it has been suggested that a-and b-tubulin stably associate with RhoH, which, in turn, associates stably with Syk and PLCg2 (54), and Syk has been shown to associate with microtubules (55,56).…”

“…It has recently been shown to bind calcium (27). Because Swip-1 colocalized with BCR and enhanced BCR-induced apoptosis (22), we hypothesized that Swip-1 controls proximal BCR signaling.…”

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

“…Another point in this direction is the recently described resistance of hippocampal neurons expressing the calcium-binding protein secretagogin (SCGN) to neurodegeneration (Attems et al 2008). The parallel involvement of calcium-binding proteins and TAU, which is suggested by these data, was underlined by the recently described interaction of a novel EF-hand calcium-binding protein and TAU in the CNS (Vega et al 2008).…”

“…It has been shown that pyramidal neurons at the hippocampus expressing SCGN are greatly free of hyperphosphorylated TAU deposits (Attems et al 2008), and TAU was shown to interact with other members of the EF-hand calcium-binding protein family in mouse brain (Vega et al 2008). The calcium-binding protein SCGN has been demonstrated to be highly and specifically expressed within the islets of Langerhans (Wagner et al 2000, Cras-Meneur et al 2004.…”