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葡萄糖低代谢促使RAN翻译,并加剧C9orf72相关的ALS/FTD表型
Andrew T Nelson1, Maria Elena Cicardi1, Shashirekha S Markandaiah1
1Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
EMBO reports
|April 29, 2024
概括
在C9orf72基因的基因突变导致ALS和FTD. 这项研究揭示了大脑葡萄糖低代谢如何通过激活损害神经元并导致运动缺陷的途径来驱动疾病的进展.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 遗传学 是一个
- 代谢途径 代谢途径
背景情况:
- 在C9orf72基因突变是最常见的遗传原因的肌缩侧面硬化症 (ALS) 和前性痴呆症 (FTD).
- 大脑葡萄糖低代谢是C9orf72突变载体的已知标志,甚至在症状出现之前,但其致病作用仍然不清楚.
研究的目的:
- 研究大脑葡萄糖低代谢在C9orf72相关的ALS/FTD病变发生过程中的功能性作用.
- 探索代谢变化,二重复蛋白 (DPR) 生产和神经退行之间的联系.
主要方法:
- 利用无症状C9-BAC小鼠模型来分析大脑葡萄糖代谢和ATP水平.
- 研究了GCN2激酶激活在将葡萄糖低代谢与DPR产生和神经元功能障碍联系中的作用.
- 研究了富含氨酸的DPRs对神经元葡萄糖吸收和代谢压力的影响.
主要成果:
- 在无症状C9-BAC小鼠的大脑中,证明了葡萄糖代谢途径的改变和ATP水平的降低.
- 通过GCN2激酶激活,葡萄糖低代谢驱动DPR产生,损害患者衍生的神经元存活,并导致小鼠的运动功能障碍.
- 确定富含氨酸的DPRs可以直接抑制神经元的葡萄糖吸收,加剧代谢压力.
结论:
- 建立了能量失衡,特别是葡萄糖低代谢和C9orf72-ALS/FTD.病变发生之间的机制联系.
- 提出了一个前循环模型,其中代谢功能障碍有助于疾病进展,突出了潜在的治疗点.
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