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Wednesday, October 3, 2018 at 4:00pm
Clark Hall, 700
David Eliezier, Weill Cornell Medical College
Host: Barbara Baird
Alpha-synuclein and Tau: Structure, Function and Parkinson’s/Alzheimer's disease
The proteins alpha-synuclein and tau are linked to Parkinson's and Alzheimer’s disease by genetics and pathology, yet little is known about their normal physiological functions. Alpha-synuclein aggregation is considered key to its role in PD. Despite this, the physiological context for pathological aS assembly remains poorly understood. Understanding the earliest steps leading to aS aggregation, which likely constitute the best targets for preventing aggregation, will require a detailed understanding of the normal function of aS at the levels of both molecular structure and basic cell biology. An example of the utility of structural investigations of aS function is our discovery of Y39 as a novel phosphorylation site, and of the potential role of this phosphorylation event in driving membrane-induced synuclein aggregation, an area of rapidly growing importance. We are also utilizing cellular assays of synuclein function to enable structure-function studies and to reveal novel aspects of synuclein function in regulating vesicle exocytosis. Finally, protein interaction partners of alpha-synuclein are likely play key roles in modulating its function and possibly its aggregation as well. We are exploring the structural basis for interactions of alpha-synuclein with Rab proteins, master regulators of vesicular trafficking.
Tau is normally a microtubule binding protein, but can also bind to membrane surfaces, an interaction that may be either physiologically or pathologically relevant. Work in the lab has demonstrated that tau-membrane interactions are mediated by short amphipathic helices, which also play a role in mediating membrane-induced aggregation to tau into novel oligomeric protein-phospholipid complexes. The core of these complexes is comprised of the PHF6 and PHF6* hexapeptide motifs, but surprisingly, only the former is found in a beta-strand conformation, while the remainder of the core is ordered but does not exhibit regular secondary structure. The properties of these oligomers bear some resemblance to recently characterized membrane-induced oligomers of alpha-synuclein.