Stimulation of ?-synuclein amyloid formation by phosphatidylglycerol micellar tubules.

ABSTRACT: ?-Synuclein (?-Syn) is a presynaptic protein that is accumulated in its amyloid form in the brains of Parkinson's patients. Although its biological function remains unclear, ?-syn has been suggested to bind to synaptic vesicles and facilitate neurotransmitter release. Recently, studies have found that ?-syn induces membrane tubulation, highlighting a potential mechanism for ?-syn to stabilize highly curved membrane structures which could have both functional and dysfunctional consequences. To understand how membrane remodeling by ?-syn affects amyloid formation, we have studied the ?-syn aggregation process in the presence of phosphatidylglycerol (PG) micellar tubules, which were the first reported example of membrane tubulation by ?-syn. Aggregation kinetics, ?-sheet content, and macroscopic protein-lipid structures were observed by Thioflavin T fluorescence, circular dichroism spectroscopy and transmission electron microscopy, respectively. Collectively, the presence of PG micellar tubules formed at a stochiometric (L/P?=?1) ratio was found to stimulate ?-syn fibril formation. Moreover, transmission electron microscopy and solid-state nuclear magnetic resonance spectroscopy revealed the co-assembly of PG and ?-syn into fibril structures. However, isolated micellar tubules do not form fibrils by themselves, suggesting an important role of free ?-syn monomers during amyloid formation. In contrast, fibrils did not form in the presence of excess PG lipids (?L/P?=?50), where most of the ?-syn molecules are in a membrane-bound ?-helical form. Our results provide new mechanistic insights into how membrane tubules modulate ?-syn amyloid formation and support a pivotal role of protein-lipid interaction in the dysfunction of ?-syn.

SUBMITTER: Jiang Z 

PROVIDER: S-EPMC6125227 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature