ALS- and FTD-associated missense mutations in TBK1 differentially disrupt mitophagy.
ALS- and FTD-associated missense mutations in TBK1 differentially disrupt mitophagy.
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DOI：
10.1073/pnas.2025053118
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发表时间：
2021-06-15
影响因子：
11.1
通讯作者：
Holzbaur ELF
中科院分区：
文献类型：
--
作者：
Harding O;Evans CS;Ye J;Cheung J;Maniatis T;Holzbaur ELF
TANK结合激酶1（TBK 1）中的错义突变对该分子具有不同的生物物理和生物化学作用，并且与神经退行性疾病肌萎缩侧索硬化（ALS）和额颞叶痴呆相关。TBK 1在清除受损的线粒体中起着重要作用。在这里，我们研究了10个ALS相关的TBK 1突变对线粒体自噬关键早期阶段的影响。我们发现TBK 1的募集和激酶活性都有助于清除受损的线粒体。此外，在神经元中，TBK 1突变体的表达单独影响线粒体网络的健康。我们的研究利用疾病相关突变来进一步完善目前的线粒体自噬模型，确定激酶TBK 1和ULK 1之间的调节串扰，并提供TBK 1在神经退行性疾病发病机制中的作用的见解。TANK结合激酶1（TBK 1）是一种多功能激酶，在线粒体自噬（选择性清除受损线粒体）中发挥重要作用。TBK 1中超过90种不同的突变与肌萎缩侧索硬化症（ALS）和额颞叶痴呆症有关，包括破坏TBK 1二聚化、与线粒体自噬受体视神经磷酸酶（OPTN）相关、自激活或催化磷酸化的能力的错义突变。我们研究了ALS相关的TBK 1突变如何影响帕金森依赖性线粒体自噬，使用成像来剖析参与清除受损线粒体的分子机制。一些突变导致该途径的严重失调，而另一些突变则引起有限的破坏。消除TBK 1二聚化或激酶活性的突变不足以完全抑制线粒体自噬，而减少二聚化和激酶活性的突变更具破坏性。最终，TBK 1募集和OPTN在S177的磷酸化是自噬体膜吞噬受损线粒体所必需的。令人惊讶的是，我们发现ULK 1活性有助于OPTN在野生型或激酶失活TBK 1存在下的磷酸化。在原代神经元中，TBK 1突变体在基础条件下诱导线粒体应激;网络应激随着进一步的线粒体损伤而加剧。我们的研究进一步完善了TBK 1在线粒体自噬中的功能模型，表明一些ALS相关突变可能通过诱导线粒体应激或抑制线粒体自噬通量而导致疾病发病。在我们的试验中，其他TBK 1突变对线粒体自噬的影响要小得多，这表明细胞类型特异性效应、累积损伤或替代TBK 1依赖性途径（如先天免疫和炎症）也影响了受影响个体的ALS发展。
Missense mutations in TANK-binding kinase 1 (TBK1) have diverse biophysical and biochemical effects on the molecule and are associated with the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia. TBK1 plays an essential role in clearing damaged mitochondria. Here, we investigate the impact of 10 ALS-linked TBK1 mutations on the critical early stage of mitophagy. We find that both TBK1 recruitment and kinase activity contribute to the clearance of the damaged mitochondria. Furthermore, in neurons, expression of TBK1 mutants alone affects mitochondrial network health. Our investigation utilizes disease-linked mutations to further refine the current model of mitophagy, identifying regulatory crosstalk between the kinases TBK1 and ULK1, and providing insights into the roles of TBK1 in neurodegenerative pathogenesis. TANK-binding kinase 1 (TBK1) is a multifunctional kinase with an essential role in mitophagy, the selective clearance of damaged mitochondria. More than 90 distinct mutations in TBK1 are linked to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia, including missense mutations that disrupt the abilities of TBK1 to dimerize, associate with the mitophagy receptor optineurin (OPTN), autoactivate, or catalyze phosphorylation. We investigated how ALS-associated mutations in TBK1 affect Parkin-dependent mitophagy using imaging to dissect the molecular mechanisms involved in clearing damaged mitochondria. Some mutations cause severe dysregulation of the pathway, while others induce limited disruption. Mutations that abolish either TBK1 dimerization or kinase activity were insufficient to fully inhibit mitophagy, while mutations that reduced both dimerization and kinase activity were more disruptive. Ultimately, both TBK1 recruitment and OPTN phosphorylation at S177 are necessary for engulfment of damaged mitochondra by autophagosomal membranes. Surprisingly, we find that ULK1 activity contributes to the phosphorylation of OPTN in the presence of either wild-type or kinase-inactive TBK1. In primary neurons, TBK1 mutants induce mitochondrial stress under basal conditions; network stress is exacerbated with further mitochondrial insult. Our study further refines the model for TBK1 function in mitophagy, demonstrating that some ALS-linked mutations likely contribute to disease pathogenesis by inducing mitochondrial stress or inhibiting mitophagic flux. Other TBK1 mutations exhibited much less impact on mitophagy in our assays, suggesting that cell-type–specific effects, cumulative damage, or alternative TBK1-dependent pathways such as innate immunity and inflammation also factor into the development of ALS in affected individuals.
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DOI：
10.1093/brain/awx370
发表时间：
2018-03-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Brenner D;Yilmaz R;Müller K;Grehl T;Petri S;Meyer T;Grosskreutz J;Weydt P;Ruf W;Neuwirth C;Weber M;Pinto S;Claeys KG;Schrank B;Jordan B;Knehr A;Günther K;Hübers A;Zeller D;Kubisch C;Jablonka S;Sendtner M;Klopstock T;de Carvalho M;Sperfeld A;Borck G;Volk AE;Dorst J;Weis J;Otto M;Schuster J;Del Tredici K;Braak H;Danzer KM;Freischmidt A;Meitinger T;Strom TM;Ludolph AC;Andersen PM;Weishaupt JH;German ALS network MND-NET
通讯作者：
German ALS network MND-NET
影响因子：
29
作者：
Freischmidt, Axel;Mueller, Kathrin;Andersen, Peter M.
通讯作者：
Andersen, Peter M.
DOI：
10.1083/jcb.201008084
发表时间：
2010-11-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jin SM;Lazarou M;Wang C;Kane LA;Narendra DP;Youle RJ
通讯作者：
Youle RJ
影响因子：
5.8
作者：
Martin KR;Celano SL;Solitro AR;Gunaydin H;Scott M;O'Hagan RC;Shumway SD;Fuller P;MacKeigan JP
通讯作者：
MacKeigan JP
影响因子：
9.8
作者：
McQuin C;Goodman A;Chernyshev V;Kamentsky L;Cimini BA;Karhohs KW;Doan M;Ding L;Rafelski SM;Thirstrup D;Wiegraebe W;Singh S;Becker T;Caicedo JC;Carpenter AE
通讯作者：
Carpenter AE