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bioRxiv · 10.1101/2021.09.26.461836

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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Abstract

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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Dada, S. T., Hardenberg, M. C., Mrugalla, L. K., McKeon, M. O., Klimont, E., Michaels, T. T. C., Vendruscolo, M.. 2021-09-26. Spontaneous nucleation and fast aggregate-dependent proliferation of α-synuclein aggregates within liquid condensates at physiological pH. https://doi.org/10.1101/2021.09.26.461836

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