de Mena Lorena, Lopez-Scarim Joshua, Rincon-Limas Diego E
Department of Neurology, McKnight Brain Institute, and Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, United States.
Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, United States.
Front Mol Neurosci. 2021 Oct 25;14:772226. doi: 10.3389/fnmol.2021.772226. eCollection 2021.
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 and 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.
TAR DNA结合蛋白43（TDP-43）的核内耗竭、异常修饰及胞质聚集与一组称为TDP-43蛋白病的致命神经退行性疾病相关，这些疾病包括肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）。尽管我们对TDP-43生理功能的理解正在迅速推进，但其发病机制相关的分子机制仍知之甚少。越来越多的证据表明，内质网（ER）应激和未折叠蛋白反应（UPR）在TDP-43病理学中起重要作用。然而，虽然来自ALS和FTLD尸检患者的神经元显示TDP-43在内质网中沉积并表现出UPR激活，但来自[具体来源未提及]和TDP-43模型的数据却产生了相互矛盾的结果。在本综述中，我们将通过梳理文献中的现有证据并探讨这些差异背后的原因，来探究TDP-43病理学、内质网应激和未折叠蛋白反应之间的复杂相互作用。我们还强调了该领域未充分探索的领域和关键未解决的问题。更好地同步和整合方法、模型及机制途径对于发现TDP-43与内质网应激关系的真实本质，并最终揭示未折叠蛋白反应的全部治疗潜力至关重要。
