Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8503, Japan.
Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
Mol Brain. 2024 Oct 23;17(1):77. doi: 10.1186/s13041-024-01150-1.
Protein turnover is crucial for cell survival, and the impairment of proteostasis leads to cell death. Aging is associated with a decline in proteostasis, as the progressive accumulation of damaged proteins is a hallmark of age-related disorders such as neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We previously discovered that the declining function of the ubiquitin-proteasome system (UPS) in motor neurons contributes to sporadic ALS pathologies, such as progressive motor neuron loss, protein accumulation, and glial activation. However, the mechanisms of UPS dysfunction-induced cell damage, such as cell death and aggregation, are not fully understood. This study used transcriptome analysis of motor neurons with UPS dysfunction and found that the expression of N-myc downstream regulated 1 (NDRG1) gets upregulated by UPS dysfunction. Additionally, the upregulation of NDRG1 induces cell death in the Neuro2a mouse neuroblastoma cell line. These results suggest that NDRG1 is a potential marker for UPS dysfunction and may play a role in neurodegeneration, such as that seen in ALS.
蛋白质周转对于细胞存活至关重要，而蛋白质稳态的破坏会导致细胞死亡。随着年龄的增长，蛋白质稳态会下降，因为受损蛋白质的逐渐积累是与年龄相关的疾病（如神经退行性疾病，包括肌萎缩侧索硬化症（ALS））的标志。我们之前发现，运动神经元中泛素-蛋白酶体系统（UPS）功能的下降导致散发性 ALS 病理，如运动神经元进行性丧失、蛋白质积累和神经胶质激活。然而，UPS 功能障碍引起的细胞损伤（如细胞死亡和聚集）的机制尚不完全清楚。本研究通过 UPS 功能障碍的运动神经元转录组分析发现，UPS 功能障碍会导致 N-myc 下游调节因子 1（NDRG1）的表达上调。此外，NDRG1 的上调会诱导 Neuro2a 小鼠神经母细胞瘤细胞系发生细胞死亡。这些结果表明，NDRG1 是 UPS 功能障碍的潜在标志物，可能在神经退行性变中发挥作用，如 ALS 中所见。
