泛素蛋白酶体系统功能障碍导致的 NDRG1 上调加重了神经退行性变。

IF 3.3 3区 医学 Q2 NEUROSCIENCES Molecular Brain Pub Date : 2024-10-23 DOI:10.1186/s13041-024-01150-1
Tomonori Hoshino, Atsushi Mukai, Hirofumi Yamashita, Hidemi Misawa, Makoto Urushitani, Yoshitaka Tashiro, Shu-Ichi Matsuzawa, Ryosuke Takahashi
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引用次数: 0

摘要

蛋白质的更替对细胞的存活至关重要,而蛋白稳态受损则会导致细胞死亡。衰老与蛋白稳态的下降有关,因为受损蛋白质的逐渐积累是神经退行性疾病(包括肌萎缩性脊髓侧索硬化症(ALS))等与年龄有关的疾病的标志。我们之前发现,运动神经元中泛素-蛋白酶体系统(UPS)功能的衰退是导致渐冻人症(ALS)病变的原因之一,如渐进性运动神经元缺失、蛋白质积累和神经胶质激活。然而,UPS 功能障碍诱发细胞损伤(如细胞死亡和聚集)的机制尚未完全明了。本研究利用转录组分析了 UPS 功能障碍的运动神经元,发现 UPS 功能障碍会上调 N-myc 下游调节 1(NDRG1)的表达。此外,NDRG1 的上调会诱导 Neuro2a 小鼠神经母细胞瘤细胞系的细胞死亡。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(如渐冻人症)中发挥作用。
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NDRG1 upregulation by ubiquitin proteasome system dysfunction aggravates neurodegeneration.

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.

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来源期刊
Molecular Brain
Molecular Brain NEUROSCIENCES-
CiteScore
7.30
自引率
0.00%
发文量
97
审稿时长
>12 weeks
期刊介绍: Molecular Brain is an open access, peer-reviewed journal that considers manuscripts on all aspects of studies on the nervous system at the molecular, cellular, and systems level providing a forum for scientists to communicate their findings. Molecular brain research is a rapidly expanding research field in which integrative approaches at the genetic, molecular, cellular and synaptic levels yield key information about the physiological and pathological brain. These studies involve the use of a wide range of modern techniques in molecular biology, genomics, proteomics, imaging and electrophysiology.
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