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粉样蛋白前体蛋白超分子组合的实时异质性是由内细胞风险因子PICALM调节的

Vivek Belapurkar^1,2, H S Mahadeva Swamy^1,3, Nivedita Singh¹

¹Centre for Neuroscience, Indian Institute of Science, Bangalore, 560012, India.

Cellular and molecular life sciences : CMLS

|September 19, 2023

概括

在阿尔茨海默氏病 (AD) 病理学中至关重要的氨基基酸前体蛋白 (APP) 纳米域形成,由PICALM调节. APP的C端序列控制其纳米级的动态和相互作用,影响AD发病.

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
细胞生物学细胞生物学

背景情况:

粉样蛋白前体蛋白 (APP) 定位到纳米级域是阿尔茨海默病 (AD) 分子病理学的关键.
蛋白质相互作用调节APP表面表达,突触保留和横向贩运.
皮卡尔姆是AD的重要风险因素,可能调节APP动态.

研究的目的:

研究PICALM在调节APP纳米级动态中的作用.
确定APP的C端序列是否影响其亚突触局部化和纳米域形成.
了解APP的C端突变和PICALM如何相互作用以影响APP的动态.

主要方法:

免疫光显微镜以评估PICALM和APP在亚突触区域的局部化.
对具有C端缺失的APP突变 (APP-Δ9,APP-Δ14) 和瑞典突变 (APP-SWE) 的分析.
单粒子追踪用于评估APP及其突变体的横向扩散和纳米尺度分离.

主要成果:

PICALM局部化到突触后密度,突触前活跃区域和内细胞区域,与APP共局并形成纳米领域.
删除APP的C端Y682ENPTY687域 (APP-Δ9,APP-Δ14) 改变了APP的横向扩散和纳米尺度分离.
APP-Δ14扩散模仿了APP-SWE,而APP-Δ9扩散类似于野生类型的APP;PICALM调节的APP突变扩散.

结论:

APP的C端序列对于调节其横向扩散和可逆纳米级域形成至关重要.
皮卡姆作为APP纳米级动态的调节器,其影响根据APPC终端修改而有所不同.
这些分子相互作用和动力学有助于在阿尔茨海默氏症发病时观察到的独特模式.

关键词:

阿尔茨海默氏症是阿尔茨海默氏症的一种疾病.粉样蛋白前体蛋白是一种前体蛋白.侧向扩散是一种侧向扩散.纳米领域是纳米领域.纳米规模组织组织.这就是PICALM.风险因素风险因素单颗粒追踪器是一个单颗粒追踪器.超高分辨率显微镜的显微镜.突触 (Synapses) 是一个突触的组成部分.

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