This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Numerous neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by amyloid deposits in or external to neurons in affected areas of the brain. In Parkinson's disease, the protein alpha-synuclein (AS) is the major component of the intracellular amyloid deposits known as Lewy bodies. In vitro, this 140aa protein undergoes aggregation upon exposure to higher than ambient temperatures and/or exposure to particular conditions (solvents, low pH, certain ligands, etc.). There is evidence for the involvement of oligomeric intermediates as the major toxic structures leading to neurotoxicity. However, the mechanism(s) by which the aggregated(ing) protein damages neurons, thus affecting motor function, are still a matter of speculation. The challenge has been to identify and characterize the elusive oligomeric intermediates of AS aggregation. The dyes/fluorophores (.e.g. Thioflavin T) generally used to monitor the formation of the final amyloid fail to report the earlier species. IA number of fluorescent probes yield signals not only upon the formation of fibrils but also the intermediates of interest. Our most recent efforts have been based on ratiometric ESIPT (excited state intermolecular proton transport) probes. We have used these signals as guides for examining the protein population by AFM during the course of the reaction. A remarkable family of supermolecular structures have been observed in the progression from monomeric soluble protein to the final mature amyloid fibrils. These intermediates include spheroidal forms), circular or oblong """"""""platforms"""""""" most often exhibiting >=1 catenated segmented fibrils (""""""""fuzzy"""""""" fibers), which detach and then transform to the mature amyloid fibrils. We denote these AS aggregation intermediates as """"""""acunas"""""""", a term coined from the Spanish words """"""""amiloide"""""""" + """"""""cunas"""""""" (""""""""cradles"""""""" in English), because of the possibility that they serve to """"""""spawn"""""""" the classical amyloid fibrils and may constitute the intermediate structures responsible for cytotoxicity. We have fractionated the acunas by centrifugation, and it is these preparations that we propose for examination by cryo-EM.
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