Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins.
Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins.
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DOI：
10.1038/s41598-020-78775-4
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发表时间：
2021-01-11
影响因子：
4.6
通讯作者：
Ivanova MI
中科院分区：
文献类型：
--
作者：
Gerson JE;Linton H;Xing J;Sutter AB;Kakos FS;Ryou J;Liggans N;Sharkey LM;Safren N;Paulson HL;Ivanova MI
大脑表达的泛素（UBQLN 1、2 和 4）是高度同源的蛋白质，参与蛋白质稳态的多个方面，并与神经退行性疾病有关。研究已经证实，UBQLN2 会形成液体状冷凝物，并在致病性聚集体中积累，就像与神经退行性疾病相关的其他蛋白质一样。然而，三种大脑表达的泛素的相对凝聚体和聚集体形成尚不清楚。在这里，我们报告了体外实验、细胞模型和人脑组织分析揭示的三种泛素在聚集倾向上的不同。与其他泛素相比，UBQLN4 显示出更高的聚集倾向，并且与淀粉样蛋白一样，UBQLN4 在体外形成硫磺素 T 阳性原纤维。通过测量细胞中斑点光漂白后的荧光恢复（FRAP），我们报告所有三种泛素都经历了液-液相变。 UBQLN2 和 4 的恢复速度比 UBQLN1 慢，这表明这些大脑表达的泛素形成的缩合物具有不同的组成并经历明显的内部重排。我们的结论是，虽然所有大脑表达的泛素都表现出以凝聚物形式表现的自缔合行为，但它们遵循不同的相分离和聚集过程。我们认为，泛素从液体状到固体的连续体之间的这种变异性既揭示了泛素的正常泛素相关功能，也揭示了它们的积累和对神经退行性疾病毒性的潜在贡献。
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.
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影响因子：
16
作者：
Dao TP;Kolaitis RM;Kim HJ;O'Donovan K;Martyniak B;Colicino E;Hehnly H;Taylor JP;Castañeda CA
通讯作者：
Castañeda CA
DOI：
10.1016/j.bbapap.2010.04.001
发表时间：
2010-07
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
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通讯作者：
Koide S
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影响因子：
16.2
作者：
Mackenzie IR;Nicholson AM;Sarkar M;Messing J;Purice MD;Pottier C;Annu K;Baker M;Perkerson RB;Kurti A;Matchett BJ;Mittag T;Temirov J;Hsiung GR;Krieger C;Murray ME;Kato M;Fryer JD;Petrucelli L;Zinman L;Weintraub S;Mesulam M;Keith J;Zivkovic SA;Hirsch-Reinshagen V;Roos RP;Züchner S;Graff-Radford NR;Petersen RC;Caselli RJ;Wszolek ZK;Finger E;Lippa C;Lacomis D;Stewart H;Dickson DW;Kim HJ;Rogaeva E;Bigio E;Boylan KB;Taylor JP;Rademakers R
通讯作者：
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影响因子：
16
作者：
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通讯作者：
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影响因子：
16
作者：
Itakura E;Zavodszky E;Shao S;Wohlever ML;Keenan RJ;Hegde RS
通讯作者：
Hegde RS