Unbiased screen reveals ubiquilin-1 and -2 highly associated with huntingtin inclusions.
Unbiased screen reveals ubiquilin-1 and -2 highly associated with huntingtin inclusions.
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DOI：
10.1016/j.brainres.2013.06.006
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发表时间：
2013-08-02
期刊：
影响因子：
2.9
通讯作者：
Giasson BI
中科院分区：
文献类型：
--
作者：
Rutherford NJ;Lewis J;Clippinger AK;Thomas MA;Adamson J;Cruz PE;Cannon A;Xu G;Golde TE;Shaw G;Borchelt DR;Giasson BI
最近在肌萎缩性侧索硬化症（ALS）和ALS/痴呆患者中发现了泛素-2突变，为该蛋白在神经退行性疾病中的重要性提供了直接证据。组织学研究表明，泛素-1/ 2与多种病理包涵体有关，包括帕金森病的路易体、阿尔茨海默病的神经原纤维缠结、扩张重复疾病的多q包涵体以及与ALS和额颞叶痴呆相关的各种蛋白质病变。利用特异性泛素-2抗体和一系列与神经退行性疾病相关的蛋白质病变的转基因小鼠模型，我们发现与α-突触核蛋白、tau和其他几种类型的蛋白质内含物相比，泛素-2优先与huntingtin polyQ扩增聚集体相关。这些结果被人类脑组织切片中泛素-1和-2的类似发现所证实，泛素-1和-2在亨廷顿蛋白包涵体中被观察到积累，但在其他类型的蛋白质包涵体中很少被观察到。在培养的细胞中，泛素-2与亨廷顿蛋白/polyQ聚集体相关，但这并不受致病突变的影响。在N586-82Q-C63亨廷顿病小鼠模型中，虽然泛素蛋白可以作为伴侣蛋白穿梭蛋白降解，但在疾病进展过程中泛素-2和多q聚集蛋白之间存在持续的共定位。因此，泛素-2与亨廷顿蛋白聚集体的共定位似乎并不促进聚集体的去除。
Recently mutations in ubiquilin-2 were identified in patients with amyotrophic lateral sclerosis (ALS) and ALS/dementia providing direct evidence for the importance of this protein in neurodegenerative diseases. Histological studies have suggested that ubiquilin-1/-2 are associated with various pathological inclusions including Lewy bodies in Parkinson’s disease, neurofibrillary tangles in Alzheimer’s disease, polyQ inclusions in expansion repeat diseases and various proteinopathies associated with ALS and frontotemporal dementia. Using specific ubiquilin-2 antibodies and a series of transgenic mouse models of proteinopathies associated with neurodegenerative disease, we show that ubiquilin-2 preferentially associates with huntingtin polyQ expansion aggregates compared to α-synuclein, tau and several other types of protein inclusions. These results were confirmed by similar findings for ubiquilin-1 and -2 in human brain tissue sections, where accumulation was observed in huntingtin inclusions, but only infrequently in other types of protein inclusions. In cultured cells, ubiquilin-2 associates with huntingtin/polyQ aggregates, but this is not compromised by disease-causing mutations. Although ubiquilin proteins can function as chaperones to shuttle proteins for degradation, there is persistent co-localization between ubiquilin-2 and polyQ aggregated proteins during disease progression in the N586-82Q-C63 Huntington’s disease mouse model. Thus, the co-localization of ubiquilin-2 with the huntingtin aggregates does not appear to facilitate aggregate removal.
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影响因子：
16.2
作者：
Giasson, BI;Duda, JE;Lee, VMY
通讯作者：
Lee, VMY
影响因子：
3.5
作者：
Doi, H;Mitsui, K;Nukina, N
通讯作者：
Nukina, N
DOI：
10.1016/s1050-3862(96)00167-2
发表时间：
1996-12-01
期刊：
GENETIC ANALYSIS-BIOMOLECULAR ENGINEERING
影响因子：
--
作者：
Borchelt, DR;Davis, J;Price, DL
通讯作者：
Price, DL
影响因子：
4.8
作者：
Emmer, Kristel L.;Waxman, Elisa A.;Giasson, Benoit I.
通讯作者：
Giasson, Benoit I.
影响因子：
16
作者：
Kleijnen, MF;Shih, AH;Howley, PM
通讯作者：
Howley, PM