Protein -Protein Interactions of Synucleins: Implications for Normal Function and Neurodegenerative Disease

Synucleins are a family of three small, highly conserved proteins expressed presynaptically in the central and peripheral nervous systems. The three isoforms, alpha, beta, and gamma, are most homologous in their N-terminal ∼100 residues, which form a lipid-binding amphipathic alpha-helix. Alpha-synuclein (AS) has been implicated in learning and memory and neurodegenerative disease, thereby influencing the entire spectrum of brain function. The data presented here addresses the normal function of the synucleins as it relates to protein-protein interactions. Immunoprecipitation assays reveal that AS interacts specifically with many other proteins. The most robust of these interactions is with tubulin heterodimers; however AS does not bind to polymerized microtubules. AS also interacts with, and competitively inhibits (Ki = 21nM) Phospholipase D2 (PLD2), a phosphatidylcholine-specific phosphohydrolase that is involved in cell signaling, vesicle transport, and mitogenesis. Alpha-synuclein's inhibitory capacity is dependent upon a lipid vesicle-induced conformational shift to alpha-helix. Inhibition of PLD2 also requires a portion of the acidic C-terminus, which may directly interact with PLD2. Furthermore, inhibition may be regulated by phosphorylation of specific serine or tyrosine residues in the C-terminus. These data suggest that the interaction between AS and PLD2 is a two-step process that requires an alpha-helical conformation and a direct interaction between AS and PLD2. Finally, previous work has demonstrated that the fatty acid, arachidonate, accelerates AS self-association, a process that may be involved in Parkinson's disease. The final chapter presented here shows that arachidonate also interferes with alpha-synuclein's inhibition of PLD2.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Microbiology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Payton, Jacqueline Elise

Contributors dc:contributor

• George, Julia M.

• Biology, Neuroscience

Language dc:language

eng

Identifier

(MiAaPQ)AAI3070038

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/86641