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

By Tim Bartels, Joanna G. Choi, D. Selkoe. Nature, 2011

1,261 citations recorded by the source corpus.

Parkinson’s disease is the second most common neurodegenerative disorder. Growing evidence indicates a causative role of misfolded forms of the protein α-synuclein in the pathogenesis of Parkinson’s disease. Intraneuronal aggregates of α-synuclein occur in Lewy bodies and Lewy neurites, the cytopathological hallmarks of Parkinson’s disease and related disorders called synucleinopathies. 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 vesicles. 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.

Subfields: Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/88efe6951037e3d138a76ff25d800e448c227421

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In Neurology

1. L. Volpicelli-Daley
2. E. Masliah
3. A. Lutz
4. Christian Haass
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In Physiology

1. E. Masliah
2. A. Lutz
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4. K. Winklhofer
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Citations in the corpus

• The many faces of α-synuclein: from structure and toxicity to therapeutic target (2012, result): “Although Bartels et al.(126) reported that chemical crosslinking of native α‐syn primarily stabilized α‐syn tetramers, studies by several groups, including the work by Wang et al.”
• Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction (2023, background): “A-syn has long been defined as a ‘natively unfolded’ monomer; however, it has been demonstrated that endogenous α-syn naturally occurs in large part as a folded tetramer of about 58 KDa with little or no amyloid-like aggregation potential [7].”
• Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, positive): “…under non-denaturing conditions adopts a helically folded tetrameric structure with enhanced lipid-binding capacity and markedly reduced aggregation propensity in comparison with a -synuclein monomers, suggesting that a -synuclein tetramers are the physiological species (Bartels et al , 2011).”