The protein alpha-synuclein (aS) is implicated in the etiology of both familial and sporadic Parkinson's disease (PD). The interplay between the normal function of aS and its pathological aggregation is poorly understood, but membrane-bound forms of aS are thought to mediate its physiological function, while aggregated forms are thought to mediate the toxicity of the protein. Structurally, aS is highly malleable, adopting a highly disordered conformational ensemble when free in solution, highly helical structures when bound to phospholipids membranes and b-sheet rich conformations when aggregated into amyloid fibrils. Preventing the aggregation of aS into amyloid fibrils or potentially toxic oligomeric species is a promising strategy for the treatment of PD. The overarching goal of this research is to achieve a detailed understanding of how synuclein structural properties and transitions modulate synuclein function and toxicity and to identify specific conformational states of aS that could facilitate the design of synuclein-interacting reagents with potential therapeutic value. The current proposal is aimed at filling a newly emerged gaps in our understanding of aS structure that were created by a) the discovery of a new PD-linked aS mutation, E46K;b) the discovery that membrane-bound aS can adopt two different topologies, an extended helix and a broken helix, and the formulation of a hypothesis regarding how these two conformations may influence synuclein function;c) the discovery of new aS interaction partners thought to modulate synuclein function. To fill these gaps and to address emerging hypotheses we have developed the following specific aims: 1. To determine the effects of the most recently discovered PD-linked mutation, E46K, on structure in the free and membrane-bound forms of aS. 2. To elucidate at high resolution the extended-helix structure of membrane-bound aS. 3. To test the hypothesis that aS can mediate interactions between topologically distinct membranes of different compositions using its previously elucidated broken-helix structure. 4. To determine the effects of AARP16/19 binding on the structure of membrane-associated aS.
These aims are motivated by the opportunity to clarify how aS sequence variations influence the structure and aggregation of the protein, and by our belief that monomeric membrane-bound conformations of aS, which are more highly ordered, may be better suited to form specific interactions with potential therapeutics. This work will advance our understanding of aS structure, function, and aggregation and will provide a structural basis for the future design and identification of reagents that can stabilize monomeric aS and prevent its oligomerization and aggregation. Furthermore, the results obtained may have general implications for strategies to address protein aggregation in other age-related motor disorders and dementias.

Public Health Relevance

The protein alpha-synuclein is thought to play an important role in the etiology of Parkinson's disease. This proposal aims to improve our understanding of specific structural states of this protein, with the long-term goal of facilitating our ability to control the structural transitions of the protein in vivo. This ability is expected allow for the development of novel therapeutic strategies for the treatment of Parkinson's disease, the second most common neurodegenerative disorder, a goal with clear and significant implications for public health.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
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Biophysics of Neural Systems Study Section (BPNS)
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Chen, Wen G
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Weill Medical College of Cornell University
Schools of Medicine
New York
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Carmo-Gonçalves, Phelippe; do Nascimento, Lucas Alex; Cortines, Juliana R et al. (2018) Exploring the role of methionine residues on the oligomerization and neurotoxic properties of DOPAL-modified ?-synuclein. Biochem Biophys Res Commun 505:295-301
Lima, Vanderlei de Araújo; do Nascimento, Lucas Alex; Eliezer, David et al. (2018) Role of Parkinson's Disease-Linked Mutations and N-Terminal Acetylation on the Oligomerization of ?-Synuclein Induced by 3,4-Dihydroxyphenylacetaldehyde. ACS Chem Neurosci :
Jentsch, Julian-Alexander; Kiburu, Irene; Pandey, Kalpana et al. (2018) Structural basis of sterol binding and transport by a yeast StARkin domain. J Biol Chem 293:5522-5531
Sung, Yoon-Hui; Eliezer, David (2018) Structure and dynamics of the extended-helix state of alpha-synuclein: Intrinsic lability of the linker region. Protein Sci 27:1314-1324
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:
Ait-Bouziad, Nadine; Lv, Guohua; Mahul-Mellier, Anne-Laure et al. (2017) Discovery and characterization of stable and toxic Tau/phospholipid oligomeric complexes. Nat Commun 8:1678
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

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