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bioRxiv · 10.1101/2024.11.18.624073

Divergent effects of pathological α-synuclein truncations and mutations on phase separation

Ray, S.·Chiodaroli, C.·Farzadfard, A.·Kunka, A.·Schott, K. H.·Hertel, S.·Mojtic, K.·Klausen, L. K.·Galvagnion, C.·Buell, A. K.
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Abstract

Phase separated condensates can accelerate -synuclein (-Syn) amyloid fibril formation implicated in Parkinsons disease pathogenesis. The effects of pathological modifications, i.e., truncations and familial mutations on the thermodynamics, material properties, and the extent of amyloid aggregation within -Syn condensates remain elusive. Here, we quantitatively demonstrate that terminal truncations significantly alter -Syn phase separation, while familial mutations impart minimal effects. Spontaneous sol-gel phase transitions of the truncated -Syn variants could give rise to amyloid fibrils almost instantly within condensates, suggesting similarities between molecular interactions driving both processes. Extending our study to model coacervate and condensate systems where -Syn acts as a client, we find -Syn can dissolve coacervates and form Pickering clusters on condensate surfaces--regulating their size. Additionally, the C-terminal region of -Syn modulates nucleic acid sequestration within condensates. Together, our findings reveal diverse effects of -Syn modifications on phase separation, both in pathological and physiological contexts. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/624073v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1760f9dorg.highwire.dtl.DTLVardef@1fb155forg.highwire.dtl.DTLVardef@138402dorg.highwire.dtl.DTLVardef@1fd5229_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Ray, S., Chiodaroli, C., Farzadfard, A., Kunka, A., Schott, K. H., Hertel, S., Mojtic, K., Klausen, L. K., Galvagnion, C., Buell, A. K.. 2024-11-19. Divergent effects of pathological α-synuclein truncations and mutations on phase separation. https://doi.org/10.1101/2024.11.18.624073

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