Aggregation of a-synuclein (aS) plays an important but still poorly understood role in the pathogenesis of Parkinson's disease (PD). The normal function of aS remains unknown, but the protein binds to phospholipid membranes and is believed to regulate synaptic vesicle pool size, vesicle recycling, neurotransmitter transport and release, and synaptic plasticity. Since the discovery of the link between aS and PD, there has been great interest in identifying aS interaction partners that influence either the pathogenic or normal roles of the protein. In the past few years, a growing number of proteins, polymers, and small molecules have been reported to bind to aS and alter its aggregation kinetics and/or its lipid-associated functions. Among these are two other members of the synuclein family, B-synuclein (BS) and y-synuclein (yS). Covalent modifications also affect aS aggregation and function. However, the mechanisms by which these various binding interactions and modifications influence aS behavior are not well understood. We have shown that residual structure in free aS may play an important role in mediating the intermolecular interactions that precede amyloid fibril formation by this protein. We hypothesize that upon covalent modification or partner interactions, aS undergoes conformational changes that underlie the consequent effects on the aggregation or normal functions of the protein. We therefore propose to characterize, at high resolution, the structural changes that occur in aS as a function of its modifications and its interactions with different partners, with an initial focus on (BS, yS, histones, HSP70, PLD2, copper and other metals and polycations. We also propose to elucidate in detail the structure of (BS and yS in their free and lipid-bound states to clarify why aS exhibits different self-assembly behavior from these close relatives. Finally, we plan to test our conclusions regarding the role of structural changes in aS by introducing rationally designed mutants, collaboratively, into yeast and fly models of aS toxicity and function. The proposed studies are focused on improving our understanding of the molecular mechanisms underlying PD and may suggest strategies for developing new PD therapeutics. The results may have broader implications for understanding and treating other amyloid diseases, including Alzheimer's disease and the prion diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG019391-06
Application #
7047811
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Monjan, Andrew A
Project Start
2001-04-01
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
6
Fiscal Year
2006
Total Cost
$302,676
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Lv, Guohua; Kumar, Ashutosh; Huang, Yun et al. (2018) A Protofilament-Protofilament Interface in the Structure of Mouse ?-Synuclein Fibrils. Biophys J 114:2811-2819
Eliezer, David (2017) Proteins acting out of (dis)order. Elife 6:
Wragg, Rachel T; Parisotto, Daniel A; Li, Zhenlong et al. (2017) Evolutionary Divergence of the C-terminal Domain of Complexin Accounts for Functional Disparities between Vertebrate and Invertebrate Complexins. Front Mol Neurosci 10:146
Villarreal-Ramirez, Eduardo; Eliezer, David; Garduño-Juarez, Ramon et al. (2017) Phosphorylation regulates the secondary structure and function of dentin phosphoprotein peptides. Bone 95:65-75
Snead, David; Lai, Alex L; Wragg, Rachel T et al. (2017) Unique Structural Features of Membrane-Bound C-Terminal Domain Motifs Modulate Complexin Inhibitory Function. Front Mol Neurosci 10:154
Zhao, Jing; Huvent, Isabelle; Lippens, Guy et al. (2017) Glycan Determinants of Heparin-Tau Interaction. Biophys J 112:921-932
Dikiy, Igor; Fauvet, Bruno; Jovi?i?, Ana et al. (2016) Semisynthetic and in Vitro Phosphorylation of Alpha-Synuclein at Y39 Promotes Functional Partly Helical Membrane-Bound States Resembling Those Induced by PD Mutations. ACS Chem Biol 11:2428-37
Ardah, Mustafa T; Paleologou, Katerina E; Lv, Guohua et al. (2015) Ginsenoside Rb1 inhibits fibrillation and toxicity of alpha-synuclein and disaggregates preformed fibrils. Neurobiol Dis 74:89-101
Eliezer, David (2012) Distance information for disordered proteins from NMR and ESR measurements using paramagnetic spin labels. Methods Mol Biol 895:127-38
Hejjaoui, Mirva; Butterfield, Sara; Fauvet, Bruno et al. (2012) Elucidating the role of C-terminal post-translational modifications using protein semisynthesis strategies: ýý-synuclein phosphorylation at tyrosine 125. J Am Chem Soc 134:5196-210

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