2011). Upon deletion of the C-terminal negative charges or addition of NaCl, the electrostatic repulsion is reduced or shielded and intermolecular interactions centered upon this region is able to occur. Then, intermolecular interactions involving Tyr136 are initiated, probably due to the aromatic hydrophobic (Makin et al. 2005; Levy et

al. 2006; Yagi et al. 2008, 2010) or π–π ring stacking interaction (Levy et al. 2006). The commitment of Tyr136 in this step is very important for fibril formation. From this increased intermolecular interaction, the fibril core region (Ala76–Lys96) (Yagi et al. 2010), which is relatively close to the C-terminal Inhibitors,research,lifescience,medical region, now begins to form the Inhibitors,research,lifescience,medical fibril nucleus. Once the fibril nucleus forms tightly, fibril extension reaction begins rapidly. During this extension

step, Tyr136 also affects the fibril extension rate through aromatic ring interactions. For the C-terminal truncation mutants that lack both negative charges and Tyr136, fibrillation must wait until the hydrophobic characteristics of the fibril core region trigger molecular association. Thus, the negative charges and Tyr136 located in the C-terminal region of α-syn both play critical roles in the mechanism Inhibitors,research,lifescience,medical of amyloid fibril formation. Figure 8 A schematic model of α-syn fibril formation mechanism. Roles of the C-terminal negative charges and Tyr136 on the fibril formation, especially on the fibril nucleus formation step, are shown. The long

blue squares represent the fibril core region … Finally, these findings in this study may shed light on the gradual and persistent fibrillation mechanism of this intrinsically disordered protein, and also may lead to the development Inhibitors,research,lifescience,medical of a medical treatment for Parkinson’s disease. In our hands, a mutant α-syn in which the amino acid residues between 119 and 140 have been deleted (Syn118) readily forms fibrils. In contrast, Syn119-140CF/Y136A, where the relevant amino acids in the same sequence region (negatively charged residues, Inhibitors,research,lifescience,medical and Tyr136) have been substituted, else is unable to form fibrils (Fig. 6). This comparison seems to suggest that the charge-neutralized, tyrosine-deleted C-terminal region of Syn119-140CF/Y136A may be actively NVP-AUY922 nmr inhibiting the fibril formation of α-syn, perhaps through intramolecular or intermolecular interaction with the fibril core sequence (residues Ala76–Lys96; Yagi et al. 2010). If true, a synthetic peptide corresponding to the C-terminal amino acid sequence of Syn119-140CF/Y136A might conceivably be utilized as an inhibitor of fibrillation, i.e., such peptide administered in vivo may interact with α-syn and prevent intermolecular interactions. Through utilization of this peptide, a new medical treatment for Parkinson’s disease may eventually be developed.