Spontaneous nucleation and fast aggregate-dependent proliferation of α-synuclein aggregates within liquid condensates at physiological pH
Dada, S. T.; Hardenberg, M. C.; Mrugalla, L. K.; McKeon, M. O.; Klimont, E.; Michaels, T. T. C.; Vendruscolo, M.
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It is well-established that -synuclein aggregation may proceed through an initial lipid-dependent aggregate formation and, if at acidic pH, a subsequent aggregate-dependent proliferation. It has also been recently reported that the aggregation of -synuclein may also take place through an alternative pathway, which takes place within dense liquid condensates produced through liquid-liquid phase separation. The microscopic mechanism of this process, however, remains to be clarified. Here, we developed a fluorescence-based assay to perform a kinetic analysis of the aggregation process of -synuclein within liquid condensates, and applied it to determine the corresponding mechanism of aggregation. Our analysis shows that at pH 7.4 the aggregation process of -synuclein within dense condensates starts with spontaneous primary nucleation followed by rapid aggregate-dependent proliferation. Taken together, these results reveal a highly efficient pathway for the appearance and proliferation of -synuclein aggregates at physiological pH.
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