ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43.
ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43.
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DOI：
10.1038/ncomms4996
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发表时间：
2014-06-03
影响因子：
16.6
通讯作者：
Miller, Christopher C. J.
中科院分区：
文献类型：
--
作者：
Stoica, Radu;De Vos, Kurt J.;Paillusson, Sebastien;Mueller, Sarah;Sancho, Rosa M.;Lau, Kwok-Fai;Vizcay-Barrena, Gema;Lin, Wen-Lang;Xu, Ya-Fei;Lewis, Jada;Dickson, Dennis W.;Petrucelli, Leonard;Mitchell, Jacqueline C.;Shaw, Christopher E.;Miller, Christopher C. J.
线粒体和内质网（ER）形成紧密的结构关联，这些促进了许多细胞功能。然而，ER区域与线粒体结合的机制还不清楚。了解这些机制不仅对理解基本的生理过程很重要，而且对理解某些疾病状态下的致病过程也很重要。特别是，ER-线粒体缔合的破坏与一些神经退行性疾病有关。在这里，我们表明，ER驻留蛋白VAPB与线粒体蛋白酪氨酸磷酸酶相互作用蛋白-51（PTPIP 51）相互作用，以调节ER-线粒体协会。此外，我们证明，TDP-43，一种与肌萎缩侧索硬化症和额颞叶痴呆症病理相关的蛋白质扰乱ER-线粒体相互作用，这与VAPB-PTPIP 51相互作用和细胞Ca 2+稳态的破坏有关。最后，我们发现TDP-43的过表达导致糖原合成酶激酶-3 β（GSK-3β）的激活，并且GSK-3β调节VAPB-PTPIP 51相互作用。我们的研究结果描述了TDP-43的一种新的致病机制。 蛋白质TDP-43的突变与肌萎缩侧索硬化症有关。在这里，作者表明突变TDP-43通过改变线粒体蛋白PTPIP 51和内质网蛋白VAPB之间的相互作用来扰乱内质网（ER）-线粒体缔合。
Mitochondria and the endoplasmic reticulum (ER) form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER–mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER–mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER–mitochondria interactions and that this is associated with disruption to the VAPB–PTPIP51 interaction and cellular Ca2+ homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3β (GSK-3β) and that GSK-3β regulates the VAPB–PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43. Mutations in the protein TDP-43 are implicated in amyotrophic lateral sclerosis. Here, the authors show that mutant TDP-43 perturbs endoplasmic reticulum (ER)–mitochondria associations by altering interactions between the mitochondrial protein PTPIP51 and the ER protein VAPB.
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影响因子：
3.5
作者：
De Vos KJ;Mórotz GM;Stoica R;Tudor EL;Lau KF;Ackerley S;Warley A;Shaw CE;Miller CC
通讯作者：
Miller CC
DOI：
10.1083/jcb.200911024
发表时间：
2010-08-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Friedman JR;Webster BM;Mastronarde DN;Verhey KJ;Voeltz GK
通讯作者：
Voeltz GK
阿尔茨海默氏病的GSK3假设。
影响因子：
4.7
作者：
Hooper C;Killick R;Lovestone S
通讯作者：
Lovestone S
影响因子：
11.4
作者：
Area-Gomez, Estela;Castillo, Maria Del Carmen Lara;Tambini, Marc D.;Guardia-Laguarta, Cristina;de Groof, Ad J. C.;Madra, Moneek;Ikenouchi, Junichi;Umeda, Masato;Bird, Thomas D.;Sturley, Stephen L.;Schon, Eric A.
通讯作者：
Schon, Eric A.
影响因子：
7.5
作者：
Kornmann, Benoit
通讯作者：
Kornmann, Benoit