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

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 ag...

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Autores principales:	Julia E. Gerson, Hunter Linton, Jiazheng Xing, Alexandra B. Sutter, Fayth S. Kakos, Jaimie Ryou, Nyjerus Liggans, Lisa M. Sharkey, Nathaniel Safren, Henry L. Paulson, Magdalena I. Ivanova
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fcee382d1ef546399d85f2b4630abc8a
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spelling	oai:doaj.org-article:fcee382d1ef546399d85f2b4630abc8a2021-12-02T15:22:57ZShared and divergent phase separation and aggregation properties of brain-expressed ubiquilins10.1038/s41598-020-78775-42045-2322https://doaj.org/article/fcee382d1ef546399d85f2b4630abc8a2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78775-4https://doaj.org/toc/2045-2322Abstract 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. Here 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 these 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 aggregation. We suggest that this variability among ubiquilins along the continuum from liquid-like to solid informs both the normal ubiquitin-linked functions of ubiquilins and their accumulation and potential contribution to toxicity in neurodegenerative diseases.Julia E. GersonHunter LintonJiazheng XingAlexandra B. SutterFayth S. KakosJaimie RyouNyjerus LiggansLisa M. SharkeyNathaniel SafrenHenry L. PaulsonMagdalena I. IvanovaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Julia E. Gerson Hunter Linton Jiazheng Xing Alexandra B. Sutter Fayth S. Kakos Jaimie Ryou Nyjerus Liggans Lisa M. Sharkey Nathaniel Safren Henry L. Paulson Magdalena I. Ivanova Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins
description	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. Here 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 these 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 aggregation. We suggest that this variability among ubiquilins along the continuum from liquid-like to solid informs both the normal ubiquitin-linked functions of ubiquilins and their accumulation and potential contribution to toxicity in neurodegenerative diseases.
format	article
author	Julia E. Gerson Hunter Linton Jiazheng Xing Alexandra B. Sutter Fayth S. Kakos Jaimie Ryou Nyjerus Liggans Lisa M. Sharkey Nathaniel Safren Henry L. Paulson Magdalena I. Ivanova
author_facet	Julia E. Gerson Hunter Linton Jiazheng Xing Alexandra B. Sutter Fayth S. Kakos Jaimie Ryou Nyjerus Liggans Lisa M. Sharkey Nathaniel Safren Henry L. Paulson Magdalena I. Ivanova
author_sort	Julia E. Gerson
title	Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins
title_short	Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins
title_full	Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins
title_fullStr	Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins
title_full_unstemmed	Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins
title_sort	shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/fcee382d1ef546399d85f2b4630abc8a
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Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins

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