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

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      Nature

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          Abstract

          Parkinson disease (PD) is the second most common neurodegenerative disorder 1, 2 . Growing evidence suggests a causative role of misfolded forms of the protein, α-synuclein (αSyn), in the pathogenesis of PD 3, 4 . Intraneuronal aggregates of αSyn occur in Lewy bodies and Lewy neurites 5 , the cytopathological hallmarks of PD and the related disorders called synucleinopathies. αSyn has long been defined as a “natively unfolded” monomer of ∼14 kDa 6 that is believed to acquire α-helical secondary structure only upon binding to lipid vesicles 7 . 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 αSyn isolated and analyzed 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 ∼58 kDa. Multiple methods, including analytical ultracentrifugation, scanning transmission electron microscopy and in vivo cell crosslinking, confirmed the occurrence of the tetramer. Native, cell-derived αSyn showed α-helical structure without lipid addition and had much greater lipid binding capacity than the recombinant αSyn studied heretofore. Whereas recombinantly expressed monomers readily aggregated into amyloid-like fibrils in vitro, native human tetramers underwent little or no amyloid-like aggregation. Based on these findings, we propose that destabilization of the helically folded tetramer precedes αSyn misfolding and aggregation in PD and other human synucleinopathies and that small molecules which stabilize the physiological tetramer could reduce αSyn pathogenicity.

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          Alpha-synuclein in Lewy bodies.

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            Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes.

            alpha-Synuclein is a highly conserved presynaptic protein of unknown function. A mutation in the protein has been causally linked to Parkinson's disease in humans, and the normal protein is an abundant component of the intraneuronal inclusions (Lewy bodies) characteristic of the disease. alpha-Synuclein is also the precursor to an intrinsic component of extracellular plaques in Alzheimer's disease. The alpha-synuclein sequence is largely composed of degenerate 11-residue repeats reminiscent of the amphipathic alpha-helical domains of the exchangeable apolipoproteins. We hypothesized that alpha-synuclein should associate with phospholipid bilayers and that this lipid association should stabilize an alpha-helical secondary structure in the protein. We report that alpha-synuclein binds to small unilamellar phospholipid vesicles containing acidic phospholipids, but not to vesicles with a net neutral charge. We further show that the protein associates preferentially with vesicles of smaller diameter (20-25 nm) as opposed to larger (approximately 125 nm) vesicles. Lipid binding is accompanied by an increase in alpha-helicity from 3% to approximately 80%. These observations are consistent with a role in vesicle function at the presynaptic terminal.
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              Missing pieces in the Parkinson's disease puzzle.

              Parkinson's disease is a neurodegenerative process characterized by numerous motor and nonmotor clinical manifestations for which effective, mechanism-based treatments remain elusive. Here we discuss a series of critical issues that we think researchers need to address to stand a better chance of solving the different challenges posed by this pathology.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                2 August 2011
                14 August 2011
                01 March 2012
                : 477
                : 7362
                : 107-110
                Affiliations
                Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
                Author notes
                [* ]Corresponding author: Dennis J. Selkoe, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. dselkoe@ 123456rics.bwh.harvard.edu
                Article
                nihpa313099
                10.1038/nature10324
                3166366
                21841800
                11d7b89c-8fb6-4ac7-ab3a-a173ff817cbf

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: R01 NS051318-02 || NS
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