Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia.
Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia.
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DOI：
10.1111/acel.13549
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发表时间：
2022-03
期刊：
影响因子：
7.8
通讯作者：
Miller CCJ
中科院分区：
文献类型：
--
作者：
Gomez-Suaga P;Mórotz GM;Markovinovic A;Martín-Guerrero SM;Preza E;Arias N;Mayl K;Aabdien A;Gesheva V;Nishimura A;Annibali A;Lee Y;Mitchell JC;Wray S;Shaw C;Noble W;Miller CCJ
C9 orf 72中的六核苷酸重复扩增是家族性肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的最常见原因。扩增引起疾病的机制尚未得到正确理解，但一个有利的途径涉及其翻译成二肽重复（DPR）多肽，其中一些是神经毒性的。然而，突变体C9 orf 72和DPR毒性的精确靶点尚不完全清楚，并且已经描述了对几种神经元功能的损伤。这些功能中的许多是通过内质网（ER）和线粒体之间的信号传导来调节的。ER-线粒体信号传导需要两个细胞器之间的密切物理接触，这是由VAPB-PTPIP 51“拴系”蛋白介导的。在这里，我们发现，在来自携带ALS/FTD致病性C9 orf 72扩增的患者的诱导多能干细胞（iPS）的神经元中，以及在突变型C9 orf 72转基因小鼠的受影响神经元中，ER-线粒体信号传导和VAPB-PTPIP 51系链被破坏。在这些小鼠中，VAPB-PTPIP 51系链的破坏发生在疾病发作之前，这表明它有助于致病过程。我们还表明，神经毒性DPR破坏了VAPB-PTPIP 51相互作用和ER-线粒体接触，这可能涉及糖原合成酶激酶-3 β（GSK 3 β）的激活，这是一种已知的VAPB-PTPIP 51结合的负调节因子。最后，我们表明这些DPR破坏了Ca 2+从ER商店到线粒体的递送，这是VAPB-PTPIP 51系链的主要功能。这种递送调节ALS/FTD中受损的许多关键神经元功能，包括生物能量学、自噬和突触功能。我们的研究结果揭示了突变C9 orf 72介导的毒性的新分子靶点。描述ALS/FTD-突变型C9 orf 72与VAPB-PTPIP 51相互作用、突触活性和神经退行性变破坏相关机制的模型。C9 orf 72衍生的毒性DPR激活GSK 3 β，导致VAPB-PTPIP 51系链断裂。这扰乱了IP 3受体介导的Ca 2+从ER到线粒体的递送，从而损害突触功能并诱导神经变性。ALS/FTD连接的TDP-43和FUS也通过激活GSK 3 β破坏VAPB-PTPIP 51相互作用（Nature Communications，5，3996; EMBO Reports，17，1326）。
Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER‐mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB‐PTPIP51 ‘tethering’ proteins. Here, we show that ER‐mitochondria signalling and the VAPB‐PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB‐PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB‐PTPIP51 interaction and ER‐mitochondria contacts and that this may involve activation of glycogen synthase kinases‐3β (GSK3β), a known negative regulator of VAPB‐PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca2+ from ER stores to mitochondria, which is a primary function of the VAPB‐PTPIP51 tethers. This delivery regulates a number of key neuronal functions that are damaged in ALS/FTD including bioenergetics, autophagy and synaptic function. Our findings reveal a new molecular target for mutant C9orf72‐mediated toxicity. Model depicting mechanisms linking ALS/FTD‐mutant C9orf72 with disruption of the VAPB‐PTPIP51 interaction, synaptic activity and neurodegeneration. C9orf72‐derived toxic DPRs activate GSK3β leading to breaking of the VAPB‐PTPIP51 tethers. This perturbs IP3 receptor‐mediated delivery of Ca2+ from ER to mitochondria to damage synaptic function and induce neurodegeneration. ALS/FTD linked TDP‐43 and FUS also disrupt the VAPB‐PTPIP51 interaction via activation of GSK3β (Nature Communications, 5, 3996; EMBO Reports, 17, 1326).
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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
影响因子：
3.5
作者：
Lee YB;Baskaran P;Gomez-Deza J;Chen HJ;Nishimura AL;Smith BN;Troakes C;Adachi Y;Stepto A;Petrucelli L;Gallo JM;Hirth F;Rogelj B;Guthrie S;Shaw CE
通讯作者：
Shaw CE
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
影响因子：
13.6
作者：
Fumagalli L;Young FL;Boeynaems S;De Decker M;Mehta AR;Swijsen A;Fazal R;Guo W;Moisse M;Beckers J;Dedeene L;Selvaraj BT;Vandoorne T;Madan V;van Blitterswijk M;Raitcheva D;McCampbell A;Poesen K;Gitler AD;Koch P;Vanden Berghe P;Thal DR;Verfaillie C;Chandran S;Van Den Bosch L;Bullock SL;Van Damme P
通讯作者：
Van Damme P
影响因子：
14.5
作者：
Bozic, Janja;Motaln, Helena;Janez, Anja Pucer;Markic, Lara;Tripathi, Priyanka;Yamoah, Alfred;Aronica, Eleonora;Lee, Youn-Bok;Heilig, Raphael;Fischer, Roman;Thompson, Andrew J.;Goswami, Anand;Rogelj, Boris
通讯作者：
Rogelj, Boris