Disruption of endoplasmic reticulum-mitochondria tethering proteins in post-mortem Alzheimer's disease brain.
Disruption of endoplasmic reticulum-mitochondria tethering proteins in post-mortem Alzheimer's disease brain.
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阿尔茨海默病死后大脑中内质网-线粒体束缚蛋白的破坏。
DOI：
10.1016/j.nbd.2020.105020
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发表时间：
2020-09
影响因子：
6.1
通讯作者：
Miller CCJ
中科院分区：
文献类型：
--
作者：
Lau DHW;Paillusson S;Hartopp N;Rupawala H;Mórotz GM;Gomez-Suaga P;Greig J;Troakes C;Noble W;Miller CCJ
内质网（ER）和线粒体之间的信号传导调节许多关键的神经元功能，其中许多在阿尔茨海默病中受到干扰。此外，在阿尔茨海默病的细胞和转基因模型中观察到对ER-线粒体信号传导的损害。然而，到目前为止，几乎没有证据表明ER-线粒体信号在人类阿尔茨海默病大脑中发生了改变。ER-线粒体信号传导由整合的ER蛋白VAPB和线粒体外膜蛋白PTPIP 51之间的相互作用介导，所述相互作用用于将ER的区域募集和“拴系”到线粒体表面。现在已知VAPB-PTPIP 51系链调节许多ER-线粒体信号传导功能，包括将Ca 2+从ER储存递送至线粒体、线粒体ATP产生、自噬和突触活性。在这里，我们研究了VAPB-PTPIP 51栓系在死后控制和阿尔茨海默病的大脑。通过免疫印迹定量ER-线粒体信号传导蛋白揭示了在终末期阿尔茨海默病中皮质而非小脑中VAPB和PTPIP 51的丢失。邻近连接测定用于量化对照、Braak III-IV期（早期/中期痴呆）和Braak VI期（严重痴呆）病例中颞叶皮质锥体神经元和小脑浦肯野细胞神经元中的VAPB-PTPIP 51相互作用。锥体神经元在阿尔茨海默病中退化，而浦肯野细胞受影响较小。这些研究表明，VAPB-PTPIP 51系链在Braak III-IV期锥体细胞神经元中被破坏，但在浦肯野细胞神经元中不被破坏。因此，我们确定了一个新的致病事件在死后阿尔茨海默氏病的大脑。我们的研究结果对阿尔茨海默病的机制的影响进行了讨论。邻近连接测定揭示，在早期（Braak阶段III-IV）阿尔茨海默病中，VAPB-PTPIP 51相互作用在颞叶皮层锥体神经元中被破坏。我们将VAPB-PTPIP 51 ER-线粒体系链的损伤鉴定为阿尔茨海默病中的新的致病事件。VAPB-PTPIP 51系链的破坏可能有助于阿尔茨海默病的神经退行性过程
Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions, many of which are perturbed in Alzheimer's disease. Moreover, damage to ER-mitochondria signaling is seen in cell and transgenic models of Alzheimer's disease. However, as yet there is little evidence that ER-mitochondria signaling is altered in human Alzheimer's disease brains. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and “tether” regions of ER to the mitochondrial surface. The VAPB-PTPIP51 tethers are now known to regulate a number of ER-mitochondria signaling functions including delivery of Ca2+from ER stores to mitochondria, mitochondrial ATP production, autophagy and synaptic activity. Here we investigate the VAPB-PTPIP51 tethers in post-mortem control and Alzheimer's disease brains. Quantification of ER-mitochondria signaling proteins by immunoblotting revealed loss of VAPB and PTPIP51 in cortex but not cerebellum at end-stage Alzheimer's disease. Proximity ligation assays were used to quantify the VAPB-PTPIP51 interaction in temporal cortex pyramidal neurons and cerebellar Purkinje cell neurons in control, Braak stage III-IV (early/mid-dementia) and Braak stage VI (severe dementia) cases. Pyramidal neurons degenerate in Alzheimer's disease whereas Purkinje cells are less affected. These studies revealed that the VAPB-PTPIP51 tethers are disrupted in Braak stage III-IV pyramidal but not Purkinje cell neurons. Thus, we identify a new pathogenic event in post-mortem Alzheimer's disease brains. The implications of our findings for Alzheimer's disease mechanisms are discussed. VAPB, PTPIP51 and IP3R1 levels are reduced in temporal cortex in late-stage Alzheimer's disease Proximity ligation assays reveal that the VAPB-PTPIP51 interaction is disrupted in temporal cortex pyramidal neurons in early (Braak stage III-IV) Alzheimer's disease We identify damage to the VAPB-PTPIP51 ER-mitochondria tethers as a new pathogenic event in Alzheimer’s disease. Disruption of the VAPB-PTPIP51 tethers may contribute to the neurodegenerative process in Alzheimer’s disease
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DOI：
10.1016/j.cub.2016.12.038
发表时间：
2017-02-06
期刊：
Current biology : CB
影响因子：
--
作者：
Gomez-Suaga P;Paillusson S;Stoica R;Noble W;Hanger DP;Miller CCJ
通讯作者：
Miller CCJ
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：
64.8
作者：
Israel, Mason A.;Yuan, Shauna H.;Bardy, Cedric;Reyna, Sol M.;Mu, Yangling;Herrera, Cheryl;Hefferan, Michael P.;Van Gorp, Sebastiaan;Nazor, Kristopher L.;Boscolo, Francesca S.;Carson, Christian T.;Laurent, Louise C.;Marsala, Martin;Gage, Fred H.;Remes, Anne M.;Koo, Edward H.;Goldstein, Lawrence S. B.
通讯作者：
Goldstein, Lawrence S. B.
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
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.