Four Exemplary Tips For MS-275
The synuclein family comprises three different isoforms [22]. Although our previous study demonstrated that the ��- and ��-Syn isoforms equivalently stimulate GSK-3��-mediated phosphorylation of tau, the ��-Syn isoform was found to have no stimulatory effects on tau phosphorylation by GSK-3�� [21]. The common participation of the ��- and ��-Syn isoforms in tau phosphorylation by GSK-3�� may be attributable to their structural features. ��-Syn http://www.selleckchem.com/products/MS-275.html is an intrinsically unfolded protein with an N-terminal domain (residues 1�C60) comprising seven imperfect KTKEGV sequence repeats, a middle hydrophobic domain (residues 61�C95) termed the non-Abeta component (NAC) domain, and a C-terminal domain with a large proportion of acidic residues (residues 96�C140) [22]. Among the three Syn isoforms, the amino acid sequences of the N-terminal amphipathic regions and the hydrophobic NAC domain are well conserved. However, the C-terminal region of ��-Syn does not match those of the other two isoforms. Although tau binds only to the acidic C-terminal domain of ��-Syn, GSK-3�� binds to the N-terminal region containing both the KTEGV repeat and the NAC domain [21]. Thus, ��-Syn may not be able to form tripartite complexes with tau and GSK-3��, perhaps accounting for its lack of any stimulatory effect on tau phosphorylation GDC-0449 ic50 by GSK-3��. Previously, it was revealed that ��-Syn and ��-Syn exhibit similar levels of expression, although ��-Syn mRNA decreases and ��-Syn mRNA increases in an age-dependent manner [44, 45]. On the other hand, a comparative study has demonstrated an increase in the level of ��-Syn mRNA and a decrease in the level of ��-Syn mRNA in the substantia nigra of patients with PD, DLBD, and LBVAD [25]. Moreover, it has been reported that ��-Syn is undetectable in LB, whereas the sequence homology and structure of ��-Syn are similar to those of ��-Syn [46]. From all of these observations, it has been suggested that ��-Syn- or ��-Syn-mediated hyperphosphorylation Quinapyramine of tau may occur in different neurodegenerative diseases. However, the specificity and physiopathological significance of ��- and ��-Syn for hyperphosphorylation of tau remain to be elucidated. It seems likely that ��-Syn protein expression is upregulated by oxidative stress and mitochondrial dysfunction [42]. Under physiological conditions, the concentration of ��-Syn in neurons is estimated to be 70�C140?��M [47], whereas the normal concentration of tau is estimated to be approximately 2?��M [48, 49]. Thus, under normal conditions, the molar ratio of tau to ��-Syn is 1?:?35�C1?:?70. Our previous study has indicated that the optimum molar ratio of ��-Syn and tau for inducing maximum phosphorylation by GSK-3�� is 1?:?20 [21]. Thus, ��-Syn-mediated hyperphosphorylation of tau by GSK-3�� may occur only when ��-Syn is present at high concentrations induced by cellular stresses, such as oxidative stress and mitochondrial dysfunction.
