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α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation

Nature volume 477, pages 107110 (01 September 2011) | Download Citation


Parkinson’s disease is the second most common neurodegenerative disorder1,2. Growing evidence indicates a causative role of misfolded forms of the protein α-synuclein in the pathogenesis of Parkinson’s disease3,4. Intraneuronal aggregates of α-synuclein occur in Lewy bodies and Lewy neurites5, the cytopathological hallmarks of Parkinson’s disease and related disorders called synucleinopathies4. α-Synuclein has long been defined as a ‘natively unfolded’ monomer of about 14 kDa (ref. 6) that is believed to acquire α-helical secondary structure only upon binding to lipid vesicles7. This concept derives from the widespread use of recombinant bacterial expression protocols for in vitro studies, and of overexpression, sample heating and/or denaturing gels for cell culture and tissue studies. In contrast, we report that endogenous α-synuclein isolated and analysed under non-denaturing conditions from neuronal and non-neuronal cell lines, brain tissue and living human cells occurs in large part as a folded tetramer of about 58 kDa. Several methods, including analytical ultracentrifugation, scanning transmission electron microscopy and in vitro cell crosslinking confirmed the occurrence of the tetramer. Native, cell-derived α-synuclein showed α-helical structure without lipid addition and had much greater lipid-binding capacity than the recombinant α-synuclein studied heretofore. Whereas recombinantly expressed monomers readily aggregated into amyloid-like fibrils in vitro, native human tetramers underwent little or no amyloid-like aggregation. On the basis of these findings, we propose that destabilization of the helically folded tetramer precedes α-synuclein misfolding and aggregation in Parkinson’s disease and other human synucleinopathies, and that small molecules that stabilize the physiological tetramer could reduce α-synuclein pathogenicity.

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Mass measurements were carried out at the Brookhaven National Laboratory STEM facility, a user facility supported by the US Department of Energy. We are grateful to D. Walker and J. Anderson (Elan Pharmaceuticals) for conducting mass spectrometry of our purified α-synuclein samples and for comments. We thank X. Simon and I. Perovic (Brandeis University) for their assistance with the AUC and phosphate analyses. Supported by NIH grants NS051318 and NS038375 (D.J.S.). We thank our colleagues at the Center for Neurologic Diseases for many discussions.

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  1. Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

    • Tim Bartels
    • , Joanna G. Choi
    •  & Dennis J. Selkoe


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All experiments were planned by T.B. and D.J.S. and conducted by T.B. and J.G.C. The manuscript was prepared by T.B. and D.J.S.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Dennis J. Selkoe.

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