TDP-43 and ER Stress in Neurodegeneration: Friends or Foes?
TDP-43 and ER Stress in Neurodegeneration: Friends or Foes?
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DOI：
10.3389/fnmol.2021.772226
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发表时间：
2021
影响因子：
4.8
通讯作者：
Rincon-Limas DE
中科院分区：
文献类型：
--
作者：
de Mena L;Lopez-Scarim J;Rincon-Limas DE
核缺失、异常修饰和TAR dna结合蛋白43 （TDP-43）的细胞质聚集与一组称为TDP-43蛋白病的致命神经退行性疾病有关，其中包括肌萎缩性侧索硬化症（ALS）和额颞叶变性（FTLD）。尽管我们对TDP-43的生理功能的了解正在迅速推进，但其发病机制的分子机制仍然知之甚少。越来越多的证据表明，内质网（ER）应激和未折叠蛋白反应（UPR）是TDP-43病理的重要参与者。然而，虽然来自尸检的ALS和FTLD患者的神经元显示内质网中有TDP-43沉积并显示UPR激活，但来自体外和体内TDP-43模型的数据产生了相互矛盾的结果。在这篇综述中，我们将通过分解文献中现有的证据并解决这些差异背后的原因，探讨TDP-43病理、内质网应激和普遍定期审议之间复杂的相互作用。我们还强调了未开发的领域和该领域未解决的关键问题。更好地同步和整合方法、模型和机制途径将是发现TDP-43和内质网应激关系的真正本质，并最终发现普遍定期审查的全部治疗潜力的关键。
Nuclear depletion, abnormal modification, and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are linked to a group of fatal neurodegenerative diseases called TDP-43 proteinopathies, which include amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Although our understanding of the physiological function of TDP-43 is rapidly advancing, the molecular mechanisms associated with its pathogenesis remain poorly understood. Accumulating evidence suggests that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are important players in TDP-43 pathology. However, while neurons derived from autopsied ALS and FTLD patients revealed TDP-43 deposits in the ER and displayed UPR activation, data originated from in vitro and in vivo TDP-43 models produced contradictory results. In this review, we will explore the complex interplay between TDP-43 pathology, ER stress, and the UPR by breaking down the evidence available in the literature and addressing the reasons behind these discrepancies. We also highlight underexplored areas and key unanswered questions in the field. A better synchronization and integration of methodologies, models, and mechanistic pathways will be crucial to discover the true nature of the TDP-43 and ER stress relationship and, ultimately, to uncover the full therapeutic potential of the UPR.
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影响因子：
12.8
作者：
Jo M;Lee S;Jeon YM;Kim S;Kwon Y;Kim HJ
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.1202922109
发表时间：
2012-04-10
影响因子：
11.1
作者：
Bilican, Bilada;Serio, Andrea;Chandran, Siddharthan
通讯作者：
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