TY - JOUR
T1 - Supramolecular non-amyloid intermediates in the early stages of α-synuclein aggregation
AU - Fauerbach, Jonathan A.
AU - Yushchenko, Dmytro A.
AU - Shahmoradian, Sarah H.
AU - Chiu, Wah
AU - Jovin, Thomas M.
AU - Jares-Erijman, Elizabeth A.
N1 - Funding Information:
This work was supported by the Max Planck Society (T.J. and E.J.-E.), the Max Planck Toxic Protein Conformation project, and the Cluster of Excellence 171 of the DFG Center for the Molecular Physiology of the Brain. E.J.-E. received support from the Argentine agencies ANpCyT, CONICET, and the University of Buenos Aires. J.F. received support from CONICET and the University of Buenos Aires. D.Y. received a fellowship from the Marie Curie Foundation. W.C. and S.S. received grants from the National Institutes of Health (P41RR002250 and PN2EY016525). S.S. was supported by a training fellowship from the Nanobiology Interdisciplinary Graduate Training Program of the W.M. Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia (NIH grant No. T32EB009379).
PY - 2012/3/7
Y1 - 2012/3/7
N2 - The aggregation of α-synuclein is associated with progression of Parkinson's disease. We have identified submicrometer supramolecular structures that mediate the early stages of the overall mechanism. The sequence of structural transformations between metastable intermediates were captured and characterized by atomic force microscopy guided by a fluorescent probe sensitive to preamyloid species. A novel ∼0.3-0.6 μm molecular assembly, denoted the acuna, nucleates, expands, and liberates fibers with distinctive segmentation and a filamentous fuzzy fringe. These fuzzy fibers serve as precursors of mature amyloid fibrils. Cryo-electron tomography resolved the acuna inner structure as a scaffold of highly condensed colloidal masses interlinked by thin beaded threads, which were perceived as fuzziness by atomic force microscopy. On the basis of the combined data, we propose a sequential mechanism comprising molecular, colloidal, and fibrillar stages linked by reactions with disparate temperature dependencies and distinct supramolecular forms. We anticipate novel diagnostic and therapeutic approaches to Parkinson's and related neurodegenerative diseases based on these new insights into the aggregation mechanism of α-synuclein and intermediates, some of which may act to cause and/or reinforce neurotoxicity.
AB - The aggregation of α-synuclein is associated with progression of Parkinson's disease. We have identified submicrometer supramolecular structures that mediate the early stages of the overall mechanism. The sequence of structural transformations between metastable intermediates were captured and characterized by atomic force microscopy guided by a fluorescent probe sensitive to preamyloid species. A novel ∼0.3-0.6 μm molecular assembly, denoted the acuna, nucleates, expands, and liberates fibers with distinctive segmentation and a filamentous fuzzy fringe. These fuzzy fibers serve as precursors of mature amyloid fibrils. Cryo-electron tomography resolved the acuna inner structure as a scaffold of highly condensed colloidal masses interlinked by thin beaded threads, which were perceived as fuzziness by atomic force microscopy. On the basis of the combined data, we propose a sequential mechanism comprising molecular, colloidal, and fibrillar stages linked by reactions with disparate temperature dependencies and distinct supramolecular forms. We anticipate novel diagnostic and therapeutic approaches to Parkinson's and related neurodegenerative diseases based on these new insights into the aggregation mechanism of α-synuclein and intermediates, some of which may act to cause and/or reinforce neurotoxicity.
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U2 - 10.1016/j.bpj.2012.01.051
DO - 10.1016/j.bpj.2012.01.051
M3 - Article
C2 - 22404935
AN - SCOPUS:84858015896
SN - 0006-3495
VL - 102
SP - 1127
EP - 1136
JO - Biophysical journal
JF - Biophysical journal
IS - 5
ER -