Regardless, correlations between transglutaminase activity and MT

Regardless, correlations between transglutaminase activity and MT stability in WT and TG2 KO mouse models are consistent with our hypothesis that transglutaminase activity is a major contributor to stable MT formation in vivo. Eighth, transglutaminase activity and TG2 protein levels correlate with MT stability during development and maturation in vivo. As axons mature and neuronal connections stabilize in response to KRX-0401 mouse various postnatal modifiers, such as myelination, cold/Ca2+-insoluble tubulin levels increase (Kirkpatrick and Brady, 1994; Kirkpatrick

et al., 2001). Correspondingly, transglutaminase protein levels and enzymatic activity are elevated (Figure 9). This suggests that developmental regulation of transglutaminase contributes to MT stabilization as the brain matures. The role for transglutaminase activity and polyamines in stabilization of axonal MTs does not preclude their playing other roles in the nervous system. Transglutaminases are proposed to be involved in neuronal development (Bailey and Johnson, 2004; Maccioni and Seeds, 1986; Mahoney et al., 2000; Tucholski et al., 2001) and signaling (Basso et al., 2012; Dai et al., 2008; Facchiano et al., 2010), as well as in neurodegenerative diseases (Bailey et al., 2005; Basso et al., 2012; De Vivo et al., 2009; Ruan and Johnson, 2007). Transglutaminase activity

and polyamine levels correlate with brain maturation, neuronal differentiation, and this website formation of neurites (Bailey and Johnson, 2004), but the underlying mechanisms are unclear. Here we propose that a key pathway for regulating neuronal development is modulation of MT stability by TG2-catalyzed polyamination of tubulins. Increases in both TG2 protein and Rebamipide transglutaminase activity increased stable MTs in postnatal brains (Figure 9), concurrent with myelination and stabilization of neuronal circuitry. Molecular pathways responsible for effects

of myelination on TG2 protein level and transglutaminase activity are under investigation. Transglutaminase activity may also contribute to changes in cellular morphology (Gentile et al., 1992). Depletion of polyamines results in the disappearance of actin and MT bundles (Pohjanpelto et al., 1981). Inhibition of polyamine biosynthesis results in defects of neuronal morphogenesis, whereas exogenous polyamines stimulate adult neurogenesis (Malaterre et al., 2004). All these are consistent with our findings and suggest a common pathway based in part on alteration of MT dynamics and stability through polyamination of tubulin by TG2. Stabilizing MTs by transglutaminase and polyamines has many positive aspects for normal cytoskeletal structure and function in developing brain, but may be a double-edged sword in the aging nervous system. Transglutaminase activity and polyamine levels increase in the aging brain (Lesort et al.

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