Clusterin protects neurons against intracellular proteotoxicity.
Clusterin protects neurons against intracellular proteotoxicity.
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DOI：
10.1186/s40478-017-0481-1
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发表时间：
2017-11-07
影响因子：
7.1
通讯作者：
Wilson MR
中科院分区：
文献类型：
--
作者：
Gregory JM;Whiten DR;Brown RA;Barros TP;Kumita JR;Yerbury JJ;Satapathy S;McDade K;Smith C;Luheshi LM;Dobson CM;Wilson MR
在内质网（ER）应激过程中，正常分泌的伴侣蛋白簇蛋白被重定向到细胞质中，这一观点目前已被广泛接受，尽管这种物理重定向的生理功能尚不清楚。在本研究中，我们检验了聚簇蛋白表达的增加是否能够保护神经元细胞免受细胞内蛋白聚集和细胞毒性的影响，这些特征与一系列神经退行性疾病密切相关。我们使用肌萎缩性侧索硬化症相关蛋白TDP-43作为主要模型，研究聚簇蛋白对体外互补、神经元细胞和果蝇系统中蛋白质聚集和神经毒性的影响。在体外实验中，我们发现clusterin直接与TDP-43相互作用并有效抑制其聚集，并观察到在内质网应激的神经元细胞中，clusterin与TDP-43共定位并特异性地减少细胞质内含物的数量。我们进一步发现，TDP-43在转基因果蝇神经元中的表达可诱导内质网应激，而聚簇蛋白的共表达可导致运动神经元轴突上错误定位的TDP-43的显著清除，部分恢复运动活动，并显著延长寿命。我们还发现，在果蝇的光感受器细胞中，聚簇蛋白的共表达对内质网应激依赖性的保护，可以抵抗Huntingtin-Q128和突变体（R406W）人类tau蛋白引起的蛋白质毒性。因此，我们得出结论，在模拟神经退行性疾病的特定特征的条件下，聚集蛋白表达的增加可以提供对细胞内蛋白质毒性的重要防御。本文的在线版本（10.1186/s40478-017-0481-1）包含补充材料，可供授权用户使用。
It is now widely accepted in the field that the normally secreted chaperone clusterin is redirected to the cytosol during endoplasmic reticulum (ER) stress, although the physiological function(s) of this physical relocation remain unknown. We have examined in this study whether or not increased expression of clusterin is able to protect neuronal cells against intracellular protein aggregation and cytotoxicity, characteristics that are strongly implicated in a range of neurodegenerative diseases. We used the amyotrophic lateral sclerosis-associated protein TDP-43 as a primary model to investigate the effects of clusterin on protein aggregation and neurotoxicity in complementary in vitro, neuronal cell and Drosophila systems. We have shown that clusterin directly interacts with TDP-43 in vitro and potently inhibits its aggregation, and observed that in ER stressed neuronal cells, clusterin co-localized with TDP-43 and specifically reduced the numbers of cytoplasmic inclusions. We further showed that the expression of TDP-43 in transgenic Drosophila neurons induced ER stress and that co-expression of clusterin resulted in a dramatic clearance of mislocalized TDP-43 from motor neuron axons, partially rescued locomotor activity and significantly extended lifespan. We also showed that in Drosophila photoreceptor cells, clusterin co-expression gave ER stress-dependent protection against proteotoxicity arising from both Huntingtin-Q128 and mutant (R406W) human tau. We therefore conclude that increased expression of clusterin can provide an important defense against intracellular proteotoxicity under conditions that mimic specific features of neurodegenerative disease. The online version of this article (10.1186/s40478-017-0481-1) contains supplementary material, which is available to authorized users.
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影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
4.1
作者：
Loison, F;Debure, L;Le Dréan, Y
通讯作者：
Le Dréan, Y
影响因子：
6
作者：
Greene, Michael J.;Sam, Flora;Connor, Lawreen H.
通讯作者：
Connor, Lawreen H.
影响因子：
4.8
作者：
Humphreys, DT;Carver, JA;Wilson, MR
通讯作者：
Wilson, MR
影响因子：
21.3
作者：
Cha-Molstad, Hyunjoo;Sung, Ki Sa;Hwang, Joonsung;Kim, Kyoung A.;Yu, Ji Eun;Yoo, Young Dong;Jang, Jun Min;Han, Dong Hoon;Molstad, Michael;Kim, Jung Gi;Lee, Yoon Jee;Zakrzewska, Adriana;Kim, Su-Hyeon;Kim, Sung Tae;Kim, Sun Yong;Lee, Hee Gu;Soung, Nak Kyun;Ahn, Jong Seog;Ciechanover, Aaron;Kim, Bo Yeon;Kwon, Yong Tae
通讯作者：
Kwon, Yong Tae