Transglutaminase 6: a protein associated with central nervous system development and motor function.

Transglutaminases (TG) form a family of enzymes that catalyse various post-translational modifications of glutamine residues in proteins and peptides including intra- and intermolecular isopeptide bond formation, esterification and deamidation. We have characterized a novel member of the mammalian TG family, TG6, which is expressed in a human carcinoma cell line with neuronal characteristics and in mouse brain. Besides full-length protein, alternative splicing results in a short variant lacking the second β-barrel domain in man and a variant with truncated β-sandwich domain in mouse. Biochemical data show that TG6 is allosterically regulated by Ca(2+) and guanine nucleotides. Molecular modelling indicates that TG6 could have Ca(2+) and GDP-binding sites related to those of TG3 and TG2, respectively. Localization of mRNA and protein in the mouse identified abundant expression of TG6 in the central nervous system. Analysis of its temporal and spatial pattern of induction in mouse development indicates an association with neurogenesis. Neuronal expression of TG6 was confirmed by double-labelling of mouse forebrain cells with cell type-specific markers. Induction of differentiation in mouse Neuro 2a cells with NGF or dibutyryl cAMP is associated with an upregulation of TG6 expression. Familial ataxia has recently been linked to mutations in the TGM6 gene. Autoantibodies to TG6 were identified in immune-mediated ataxia in patients with gluten sensitivity. These findings suggest a critical role for TG6 in cortical and cerebellar neurons

Transient simulation of the last glacial inception. Part II: Sensitivity and feedback analysis

The sensitivity of the last glacial-inception (around 115 kyr BP, 115,000 years before present) to different feedback mechanisms has been analysed by using the Earth system model of intermediate complexity CLIMBER-2. CLIMBER-2 includes dynamic modules of the atmosphere, ocean, terrestrial biosphere and inland ice, the last of which was added recently by utilising the three-dimensonal polythermal ice-sheet model SICOPOLIS. We performed a set of transient experiments starting at the middle of the Eemiam interglacial and ran the model for 26,000 years with time-dependent orbital forcing and observed changes in atmospheric CO2 concentration (CO2 forcing). The role of vegetation and ocean feedback, CO2 forcing, mineral dust, thermohaline circulation and orbital insolation were closely investigated. In our model, glacial inception, as a bifurcation in the climate system, appears in nearly all sensitivity runs including a run with constant atmospheric CO2 concentration of 280 ppmv, a typical interglacial value, and simulations with prescribed present-day sea-surface temperatures or vegetation cover—although the rate of the growth of ice-sheets growth is smaller than in the case of the fully interactive model. Only if we run the fully interactive model with constant present-day insolation and apply present-day CO2 forcing does no glacial inception appear at all. This implies that, within our model, the orbital forcing alone is sufficient to trigger the interglacial–glacial transition, while vegetation, ocean and atmospheric CO2 concentration only provide additional, although important, positive feedbacks. In addition, we found that possible reorganisations of the thermohaline circulation influence the distribution of inland ic