The long-term objective of this research is to develop a detailed, atomic-resolution structural and functional understanding of protein aggregation and fibrillation relevant to human disease, principally with studies of alpha-synuclein. Wild type alpha-synuclein and its mutants (A30P, E46K and A53T) associated with early- onset Parkinson's disease (PD) will be examined in several structural states, including protofibrils, fibrils and membrane-associated complexes. We propose that the chemical details of these structures determine the natural physiological function of alpha-synuclein and, in the mutants and/or under environmental stress, contribute to PD pathology. Moreover, we propose that conversion among several structural states is an essential feature of synucleins;this structural plasticity is likely to be required for neuronal development and maintenance. To examine these structures, magic-angle spinning (MAS) solid-state NMR (SSNMR) experiments will be employed, elucidating details of conformation and dynamics that are inaccessible to other experimental techniques.
Alpha-synuclein is a central player in Parkinson's disease. The precise relationships between alpha-synuclein structure and this disease are not yet well understood. Our proposed studies aim to advance this fundamental knowledge, which will assist the broader research community in developing improved diagnostic tools and therapies for Parkinson's disease.
|Comellas, Gemma; Rienstra, Chad M (2013) Protein structure determination by magic-angle spinning solid-state NMR, and insights into the formation, structure, and stability of amyloid fibrils. Annu Rev Biophys 42:515-36|
|Rienstra, Chad M (2013) Amyloid structures from Alzheimer's disease patients. Structure 21:1722-3|
|Tang, Ming; Comellas, Gemma; Rienstra, Chad M (2013) Advanced solid-state NMR approaches for structure determination of membrane proteins and amyloid fibrils. Acc Chem Res 46:2080-8|
|Lemkau, Luisel R; Comellas, Gemma; Lee, Shin W et al. (2013) Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K. PLoS One 8:e49750|
|Comellas, Gemma; Lemkau, Luisel R; Zhou, Donghua H et al. (2012) Structural intermediates during ýý-synuclein fibrillogenesis on phospholipid vesicles. J Am Chem Soc 134:5090-9|
|Lemkau, Luisel R; Comellas, Gemma; Kloepper, Kathryn D et al. (2012) Mutant protein A30P ?-synuclein adopts wild-type fibril structure, despite slower fibrillation kinetics. J Biol Chem 287:11526-32|
|Comellas, Gemma; Lopez, Jakob J; Nieuwkoop, Andrew J et al. (2011) Straightforward, effective calibration of SPINAL-64 decoupling results in the enhancement of sensitivity and resolution of biomolecular solid-state NMR. J Magn Reson 209:131-5|
|Wylie, Benjamin J; Sperling, Lindsay J; Nieuwkoop, Andrew J et al. (2011) Ultrahigh resolution protein structures using NMR chemical shift tensors. Proc Natl Acad Sci U S A 108:16974-9|
|Tang, Ming; Sperling, Lindsay J; Berthold, Deborah A et al. (2011) High-resolution membrane protein structure by joint calculations with solid-state NMR and X-ray experimental data. J Biomol NMR 51:227-33|
|Comellas, Gemma; Lemkau, Luisel R; Nieuwkoop, Andrew J et al. (2011) Structured regions of ?-synuclein fibrils include the early-onset Parkinson's disease mutation sites. J Mol Biol 411:881-95|
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