Parkinson's disease is the most common neurodegenerative movement disorder, affecting an estimated 1% of the population aged 65 and older. The protein ?-synuclein is the primary component of Lewy bodies, the neuronal cytoplasmic deposits of aggregated proteins that are the hallmark of Parkinson's disease. There is compelling evidence that the process of ?-synuclein aggregation is directly related to Parkinson's disease pathology. However, the aggregation of ?-synuclein is a complex, heterogeneous process during which multiple oligomeric protein species are populated at various timepoints and persist over a range of timescales, making its complete characterization extremely challenging. Moreover, the relationship between the various molecular species formed in the aggregation process and disease pathology is still an open question, although the direct interaction between oligomeric ?-synuclein and cellular membranes has been implicated. An additional complication comes from two recent publications that provide evidence that the native state of ?- synuclein, long believed to be a disordered monomer, may actually be a partially structured tetramer. Our hypothesis is that both the functional and dysfunctional interactions of AS are modulated by changes in the average conformational or oligomeric ensemble and the dynamic interchange between states within these ensembles. Our research will characterize these ensembles in solution (Aim 1), bound to model membranes (Aim 2), and in living cells (Aim 3), with the goal of determining physical features that are associated with th transition to toxic states. As a consequence of these experiments, we will also determine the relationship between the putative tetramer and monomer forms of AS. To do this, we will use single molecule and time- resolved fluorescence methods. Our experimental approaches have the advantage of allowing for the characterization of ?-synuclein under conditions that favor oligomerization or aggregation without the complication of signal interpretation that accompanies actual self-association of the protein. The results of our investigation will be a comprehensive view of what properties of the solution, membrane, and cellular environment favor self-association of ?-synuclein into toxic structures. Such understanding is critical to the long term goal of our research group to identify potential molecular targets for the development of therapeutics to treat or prevent Parkinson's disease.
There is compelling, although poorly understood, evidence that supports a link between the neuronal protein ?-synuclein and the development of Parkinson's disease. Here we seek to understand the relationship between the intrinsic dynamics and structures of ?-synuclein in solution and bound to membranes and its propensity to self-associate into toxic structures in disease. This work should provide insight into identifyig relevant targets for the development of therapeutics to treat this debilitating disease.
| Espinoza-Sanchez, Sofia; Metskas, Lauren Ann; Chou, Steven Z et al. (2018) Conformational changes in Arp2/3 complex induced by ATP, WASp-VCA, and actin filaments. Proc Natl Acad Sci U S A 115:E8642-E8651 |
| Ferrie, John J; Haney, Conor M; Yoon, Jimin et al. (2018) Using a FRET Library with Multiple Probe Pairs To Drive Monte Carlo Simulations of ?-Synuclein. Biophys J 114:53-64 |
| Quach, Kim; LaRochelle, Jonathan; Li, Xiao-Han et al. (2018) Unique arginine array improves cytosolic localization of hydrocarbon-stapled peptides. Bioorg Med Chem 26:1197-1202 |
| Fung, Ho Yee Joyce; Birol, Melissa; Rhoades, Elizabeth (2018) IDPs in macromolecular complexes: the roles of multivalent interactions in diverse assemblies. Curr Opin Struct Biol 49:36-43 |
| Tavoulari, Sotiria; Margheritis, Eleonora; Nagarajan, Anu et al. (2016) Two Na+ Sites Control Conformational Change in a Neurotransmitter Transporter Homolog. J Biol Chem 291:1456-71 |
| Metskas, Lauren Ann; Rhoades, Elizabeth (2016) Order-Disorder Transitions in the Cardiac Troponin Complex. J Mol Biol 428:2965-77 |
| Melo, Ana M; Coraor, Juliana; Alpha-Cobb, Garrett et al. (2016) A functional role for intrinsic disorder in the tau-tubulin complex. Proc Natl Acad Sci U S A 113:14336-14341 |
| Liu, Yuting; Cai, Yingying; Liu, Wei et al. (2015) Triblock peptide-linker-lipid molecular design improves potency of peptide ligands targeting family B G protein-coupled receptors. Chem Commun (Camb) 51:6157-60 |
| Shi, Zheng; Sachs, Jonathan N; Rhoades, Elizabeth et al. (2015) Biophysics of ?-synuclein induced membrane remodelling. Phys Chem Chem Phys 17:15561-8 |
| Espósito, Danillo L A; Nguyen, Jennifer B; DeWitt, David C et al. (2015) Physico-chemical requirements and kinetics of membrane fusion of flavivirus-like particles. J Gen Virol 96:1702-11 |
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