Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Autophagy. 2023 Aug;19(8):2403-2405. doi: 10.1080/15548627.2023.2167690. Epub 2023 Jan 18.
TTR (transthyretin) strikes a neuroprotective function in the prevention of amyloid-β (Aβ) deposition in Alzheimer disease (AD). Perturbation of the stringently controlled TARDBP/TDP-43 (TAR DNA binding protein) expression gives rise to cytoplasmic aggregation, characterized by TARDBP proteinopathy affiliated with several neurological disorders, including frontotemporal lobar degeneration with TARDBP pathology (FTLD-TDP) and amyotrophic lateral sclerosis/ALS. Proposedly, TTR can maintain cellular proteostasis susceptible to TARDBP aggregates and initiate its removal. Herein, we disclose that TTR upregulated in response to excessive TARDBP causes TARDBP aggregation in FTLD-TDP and co-accumulates with it. Moreover, TTR expression increases with age in FTLD-TDP but shows a downward decline in the elderly. TTR promotes macroautophagy/autophagy activity and facilitates aggregated TARDBP degradation via autophagy. Compellingly, TTR binds to ATF4 and boosts its nuclear import for autophagy upregulation. Therefore, TTR directs autophagy teamwork in bi-directional regulation through enhancing autophagy activity via ATF4 and chaperoning aggregated TARDBP to phagophores for degradation. Aβ: amyloid-β; AD: Alzheimer disease; ER: endoplasmic reticulum; FTLD-TDP: frontotemporal lobar degeneration with TARDBP pathology; TARDBP/TDP-43: TAR DNA binding protein; TTR: transthyretin; UPR: unfolded protein response.
转甲状腺素（TTR）在预防阿尔茨海默病（AD）中β淀粉样蛋白（Aβ）沉积方面发挥神经保护作用。严格控制的 TARDBP/TDP-43（TAR DNA 结合蛋白）表达的紊乱会导致细胞质聚集，其特征是 TARDBP 蛋白病与包括额颞叶痴呆伴 TARDBP 病理学（FTLD-TDP）和肌萎缩侧索硬化症/ALS 在内的几种神经疾病有关。据称，TTR 可以维持对 TARDBP 聚集敏感的细胞蛋白质平衡，并启动其清除。在此，我们揭示了 TTR 响应过量 TARDBP 而上调会导致 FTLD-TDP 中的 TARDBP 聚集，并与之共聚集。此外，FTLD-TDP 中 TTR 的表达随年龄增长而增加，但在老年人中则下降。TTR 通过自噬增加巨自噬/自噬活性，并促进聚集的 TARDBP 降解。引人注目的是，TTR 与 ATF4 结合并促进其核输入以增强自噬。因此，TTR 通过 ATF4 增强自噬活性并将聚集的 TARDBP 引导到吞噬体进行降解，从而在双向调节中指导自噬协同作用。Aβ：β淀粉样蛋白；AD：阿尔茨海默病；ER：内质网；FTLD-TDP：额颞叶痴呆伴 TARDBP 病理学；TARDBP/TDP-43：TAR DNA 结合蛋白；TTR：转甲状腺素；UPR：未折叠蛋白反应。
