The accumulation of α-synuclein aggregates within neurons is the pathological hallmark of Parkinson’s disease. α-Synuclein consists of three distinct regions: a positively charged N-terminal region (residues 1–60), a central hydrophobic non-amyloid-β component (NAC) region (residues 61–95), and a negatively charged C-terminal region (residues 96–140). In neuronal intracellular membranes, phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidylcholine (PC) are abundant phospholipids. Lipidomic analyses of Parkinson’s disease brains have revealed a significant reduction in PE levels, accompanied by an increase in PS. Numerous studies have shown that α-synuclein preferentially binds to negatively charged lipid membranes via electrostatic interactions involving lysine residues in the N-terminal region. However, the effect of zwitterionic phospholipid composition on the membrane binding behavior of α-synuclein remains largely elusive. In this study, we investigated the effects of negatively charged PS and zwitterionic PE on the membrane-binding properties of α-synuclein. Circular dichroism analysis showed that PS is essential for the membrane binding and the transition to α-helical structure of α-synuclein. We also found that the presence of PE significantly enhances the α-helical formation, particularly within the N-terminal 1–35 residues of α-synuclein. By using the environment-sensitive fluorescence probe, acrylodan, we further evaluated the region-specific membrane interactions of α-synuclein. The results demonstrated that in addition to the negatively charged C-terminal region, the NAC region exhibits more solvent-exposed lipid-bound conformation compared to the N-terminal region. Interestingly, the presence of PE induces more hydrophobic conformation in the N-terminal region as well as promotes association of the C-terminal region at the membrane surface. Collectively, our results indicate that not only negatively charged PS but also zwitterionic PE modulates the membrane-bound conformation both in the N-terminal and the C-terminal regions of α-synuclein.
Namba et al. (Sun,) studied this question.