Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Sci Adv. 2023 Jul 14;9(28):eadd5479. doi: 10.1126/sciadv.add5479.
Proteasomes are the central proteolytic machines that are critical for breaking down most of the damaged and abnormal proteins in human cells. Although universally applicable drugs are not yet available, the stimulation of proteasomal activity is being analyzed as a proof-of-principle strategy to increase cellular resistance to a broad range of proteotoxic stressors. These approaches have included the stimulation of proteasomes through the overexpression of individual proteasome subunits, phosphorylation, or conformational changes induced by small molecules or peptides. In contrast to these approaches, we evaluated a transcription-driven increase in the total proteasome pool to enhance the proteolytic capacity of degenerating retinal neurons. We show that overexpression of nuclear factor erythroid-2-like 1 (Nfe2l1) transcription factor stimulated proteasome biogenesis and activity, improved the clearance of the ubiquitin-proteasomal reporter, and delayed photoreceptor neuron loss in a preclinical mouse model of human blindness caused by misfolded proteins. The findings highlight Nfe2l1 as an emerging therapeutic target to treat neurodegenerative diseases linked to protein misfolding.
蛋白酶体是中央蛋白水解机器，对于降解人体细胞中大多数受损和异常的蛋白质至关重要。尽管尚未开发出普遍适用的药物，但人们正在分析刺激蛋白酶体活性作为增加细胞对广泛的蛋白毒性应激物的抵抗能力的原理验证策略。这些方法包括通过过表达单个蛋白酶体亚基、磷酸化或小分子或肽诱导的构象变化来刺激蛋白酶体。与这些方法不同，我们评估了转录驱动的总蛋白酶体池的增加，以增强退化的视网膜神经元的蛋白水解能力。我们表明，核因子红细胞 2 样 1 (Nfe2l1) 转录因子的过表达刺激了蛋白酶体的生物发生和活性，改善了泛素蛋白酶体报告物的清除，并延缓了由错误折叠蛋白引起的人类失明的临床前小鼠模型中光感受器神经元的丢失。这些发现强调了 Nfe2l1 作为一种新兴的治疗靶点，可用于治疗与蛋白质错误折叠相关的神经退行性疾病。
