3-硝基酪氨酸通过抑制线粒体的运动缩短非多巴胺能神经元的轴突。

IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemistry international Pub Date : 2024-08-16 DOI:10.1016/j.neuint.2024.105832
Masahiro Hirai , Kohei Suzuki , Yusuke Kassai , Yoshiyuki Konishi
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引用次数: 0

摘要

3-硝基酪氨酸(3-NT)是氧化和亚硝基应激的副产物,与年龄相关的神经退行性疾病有关。目前的文献表明,游离的 3-NT 会通过酪氨酸化/去酪氨酸化循环整合到 α-微管蛋白的羧基末端结构域中。与这种整合无关,3-NT 与多巴胺能神经元的细胞死亡有关。鉴于酪氨酸化/去酪氨酸化在支配轴突形态和功能方面的关键作用,在这一过程中用 3-NT 取代酪氨酸可能会破坏轴突的稳态,尽管这方面的研究仍然不足。在本研究中,我们研究了 3-NT 对小脑颗粒神经元轴突的影响,小脑颗粒神经元被用作非多巴胺能神经元的模型。我们的观察结果表明,轴突缩短与3-NT掺入α-微管蛋白有关。重要的是,这种轴突效应是在细胞死亡开始之前观察到的。此外,研究还发现 3-NT 会降低轴突内线粒体的运动性,从而导致线粒体膜电位随之降低。3-NT抑制了线粒体的运动和轴突的伸长,而抑制了负责将线粒体锚定在微管上的蛋白质--合成鞘磷脂,则恢复了线粒体的运动和轴突的伸长。这些发现强调了 3-NT 通过阻碍线粒体运动对轴突伸长的抑制作用,表明它可能参与了非多巴胺能神经元的轴突功能障碍。
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3-Nitrotyrosine shortens axons of non-dopaminergic neurons by inhibiting mitochondrial motility

3-Nitrotyrosine (3-NT), a byproduct of oxidative and nitrosative stress, is implicated in age-related neurodegenerative disorders. Current literature suggests that free 3-NT becomes integrated into the carboxy-terminal domain of α-tubulin via the tyrosination/detyrosination cycle. Independently of this integration, 3-NT has been associated with the cell death of dopaminergic neurons. Given the critical role of tyrosination/detyrosination in governing axonal morphology and function, the substitution of tyrosine with 3-NT in this process may potentially disrupt axonal homeostasis, although this aspect remains underexplored. In this study, we examined the impact of 3-NT on the axons of cerebellar granule neurons, which is used as a model for non-dopaminergic neurons. Our observations revealed axonal shortening, which correlated with the incorporation of 3-NT into α-tubulin. Importantly, this axonal effect was observed prior to the onset of cellular death. Furthermore, 3-NT was found to diminish mitochondrial motility within the axon, leading to a subsequent reduction in mitochondrial membrane potential. The suppression of syntaphilin, a protein responsible for anchoring mitochondria to microtubules, restored the mitochondrial motility and axonal elongation that were inhibited by 3-NT. These findings underscore the inhibitory role of 3-NT in axonal elongation by impeding mitochondrial movement, suggesting its potential involvement in axonal dysfunction within non-dopaminergic neurons.

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来源期刊
Neurochemistry international
Neurochemistry international 医学-神经科学
CiteScore
8.40
自引率
2.40%
发文量
128
审稿时长
37 days
期刊介绍: Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.
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