Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins

Gerson, J. E.; Linton, H.; Xing, J.; Sutter, A. B.; Kakos, F. S.; Ryou, J.; Liggans, N.; Sharkey, L.; Safren, N.; Paulson, H. L.; Ivanova, M. I.

doi:10.1101/2020.08.12.248401

bioRxiv · 10.1101/2020.08.12.248401

Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins

Gerson, J. E.·Linton, H.·Xing, J.·Sutter, A. B.·Kakos, F. S.·Ryou, J.·Liggans, N.·Sharkey, L.·Safren, N.·Paulson, H. L.·Ivanova, M. I.

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Abstract

The brain-expressed ubiquilins, UBQLNs 1, 2 and 4, are highly homologous proteins that participate in multiple aspects of protein homeostasis and are implicated in neurodegenerative diseases. Studies have established that UBQLN2 forms liquid-like condensates and accumulates in pathogenic aggregates, much like other proteins linked to neurodegenerative diseases. However, the relative condensate and aggregate formation of the three brain-expressed ubiquilins is unknown. We report that the three ubiquilins differ in aggregation propensity, revealed by in-vitro experiments, cellular models, and analysis of human brain tissue. UBQLN4 displays heightened aggregation propensity over the other ubiquilins and, like amyloids, UBQLN4 forms ThioflavinT-positive fibrils in vitro. Measuring fluorescence recovery after photobleaching (FRAP) of puncta in cells, we report that all three ubiquilins undergo liquid-liquid phase transition. UBQLN2 and 4 exhibit slower recovery than UBQLN1, suggesting the condensates formed by the brain-expressed ubiquilins have different compositions and undergo distinct internal rearrangements. We conclude that while all brain-expressed ubiquilins exhibit self-association behavior manifesting as condensates, they follow distinct courses of phase-separation and levels of aggregation. This variability among ubiquilins along the continuum from liquid-like to solid likely informs both the normal ubiquitin-linked functions of ubiquilins and their accumulation and potential contribution to toxicity in various neurodegenerative diseases.

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Gerson, J. E., Linton, H., Xing, J., Sutter, A. B., Kakos, F. S., Ryou, J., Liggans, N., Sharkey, L., Safren, N., Paulson, H. L., Ivanova, M. I.. 2020-08-13. Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins. https://doi.org/10.1101/2020.08.12.248401

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