Transglutaminase 2 accelerates neuroinflammation in amyotrophic lateral sclerosis through interaction with misfolded superoxide dismutase 1.

Although the aberrant assembly of mutant superoxide dismutase 1 (mSOD1) is implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS), the molecular basis of superoxide dismutase 1 (SOD1) oligomerization remains undetermined. We investigated the roles of transglutaminase 2 (TG2), an endogenous cross-linker in mSOD1-linked ALS. TG2 interacted preferentially with mSOD1 and promoted its oligomerization in transfected cells. Purified TG2 directly oligomerized recombinant mutant SOD1 and the apo-form of the wild-type SOD1 proteins in a calcium-dependent manner, indicating that misfolded SOD1 is a substrate of TG2. Moreover, the non-cell-autonomous effect of extracellular TG2 on the neuroinflammation was suggested, since the TG2-mediated soluble SOD1 oligomers induced tumor necrosis factor-α, interleukin-1ß, and nitric oxide in microglial BV2 cells. TG2 was up-regulated in the spinal cord of pre-symptomatic G93A SOD1 transgenic mice and in the hypoglossal nuclei of mice suffering nerve ligation. Furthermore, inhibition of spinal TG2 by cystamine significantly delayed the progression and reduced SOD1 oligomers and microglial activation. These results indicate a novel role of TG2 in SOD1 oligomer-mediated neuroinflammation, as well as in the involvement in the intracellular aggregation of misfolded SOD1 in ALS.

A novel antibacterial agent derived from the C-terminal domain of streptococcus mutans GTP-binding protein.

A decapeptide, P1, homologous to part of the Streptococcus mutans G-protein (SGP) and the Escherichia coli Era protein, was synthesized and examined for growth-inhibitory effects. When P1 10 mg/L was added to E. coli DH5, the viability of the cells was reduced by 13%. Addition of lauric acid enhanced the bactericidal effects of P1 (68% killing in the presence of P1 plus lauric acid). Similar enhancements were observed for mono lauroyl-rac-glycerol (MLG) and sodium dodecyl sulphate (SDS). In cultures treated with both P1 and MLG, there were more elongated cells than in cultures treated with detergent or peptide alone. As with E. coli, the bactericidal effects of P1 on S. mutans were significantly enhanced in the presence of the detergent lauric acid. The combination of the two effectors produced >90% killing of S. mutans. Likewise, the combined action of P1 plus lauric acid reduced the viability of Listeria monocytogenes. P1 did not appear to be toxic to human gingival epithelial cells when added at concentrations < or = 1000 mg/L. Therefore, P1 has properties which could allow it to be used as an antibacterial agent.