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早期破坏CREB通路导致FTD/ALS皮层神经元的树突形态变化

Michelle Jean Gregoire^1,2,3, Riccardo Sirtori^1,3, Liviana Donatelli^1,2,3

¹Cell and Molecular Biology Department, University of Rhode Island, Kingston, RI 02881.

Proceedings of the National Academy of Sciences of the United States of America

|November 26, 2024

概括

前性痴呆/性侧面硬化症 (FTD/ALS) 涉及由于PKA亚单元失衡而导致CREB激活受损. 恢复cAMP水平可以挽救CREB活动,改善C9-FTD/ALS模型中的神经元健康和突触功能.

科学领域:

神经科学是一个神经科学.
分子生物学分子生物学
遗传学是一个遗传学.

背景情况:

突触损失和树突退化是神经退行性疾病的标志,如阿尔茨海默氏症 (AD) 和前性痴呆症/肌性侧面硬化症 (FTD/ALS).
对于神经元的生存,突触可塑性,学习和记忆来说,cAMP-响应元素结合蛋白 (CREB) 途径至关重要,其中由蛋白激酶A (PKA) 激活CREB是一个关键步骤.
CREB通路中的功能障碍与AD有关,新出现的证据表明它与FTD/ALS有关,尽管潜在的机制尚不清楚.

研究的目的:

调查C9ORF72相关FTD/ALS中CREB活性降低的机制.
确定CREB通路损伤是否有助于FTD/ALS中的突触和树突病理.
通过探索CREB活动的调节来确定FTD/ALS的潜在治疗点.

主要方法:

利用来自具有C9ORF72六核酸重复扩张的个体的诱导多能干细胞 (iPSC) 衍生的皮层状神经元.
评估了这些iPSC衍生的神经元中的CREB激活,树突形态和突触蛋白水平.
分析了C9-ALS患者死后脑组织中的PKA亚单元比率,并检查了CREB通路功能.
实验调节的循环腺单酸盐 (cAMP) 水平高于确定的损伤.

主要成果:

来自C9ORF72 iPSC线的神经元显示CREB激活减少,导致树突和突触健康降低.
观察到的CREB损伤与PKA的调节和催化子单元的不平衡有机械联系.
这种PKA失衡和随后的CREB功能障碍在C9-ALS患者的死后脑组织中被发现是保存的.
调节cAMP水平成功地挽救了CREB活动,改善了树突形态和突触蛋白水平.

结论:

阐明了C9ORF72介导的FTD/ALS早期CREB通路功能障碍的机制.
确定了PKA子单元的不平衡是导致CREB损伤的关键因素.
证明向cAMP途径可以恢复CREB功能并改善神经元健康,为FTD/ALS和其他神经退行性疾病提供潜在的治疗策略.

关键词:

这就是ALS.克里布 (Creb) 是一个非常重要的数字.这是一个FTD.这就是PKA PKA.树突 (dendrites) 是一种树突.

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