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Abstract:
The aggregation of
a
-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
m
m 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
a
-synuclein and intermediates, some of which may act to cause and/or reinforce neurotoxicity.
