Proteins in aggregates functionally impact multiple neurodegenerative disease models by forming proteasome-blocking complexes
Proteins in aggregates functionally impact multiple neurodegenerative disease models by forming proteasome-blocking complexes
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DOI：
10.1111/acel.12296
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发表时间：
2015-02-01
期刊：
影响因子：
7.8
通讯作者：
Reis, Robert Shmookler
中科院分区：
文献类型：
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作者：
Ayyadevara, Srinivas;Balasubramaniam, Meenakshisundaram;Reis, Robert Shmookler
依赖性神经变性疾病逐渐形成含有两种共有组分的聚集体（例如，TDP-43，磷酸化tau）和对每种疾病特异的蛋白质。我们研究了不同的神经病变是否可能有额外的聚集倾向的蛋白质的共同点，可通过蛋白质组学。表达unc-54 p/Q40：：YFP的秀丽隐杆线虫是多聚谷氨酰胺阵列疾病如亨廷顿病的模型，在孵化后2- 6天在肌肉中积累聚集体。这些焦点，抗体偶联磁珠分离，其特征在于高分辨率质谱。三个Q40：：YFP相关蛋白被推断为促进聚集和细胞毒性，其RNA干扰敲低降低或延迟了性状。这些RNAi治疗还延缓了阿尔茨海默病模型、具有肌肉或泛神经元A（1-42）表达的线虫和行为表型中的聚集/细胞毒性。最丰富的聚集蛋白是富含谷氨酰胺/天冬酰胺的，有利于与其他无规卷曲结构域的疏水相互作用。一种特别有效的聚集调节剂，CRAM-1/HYPK，
Age-dependent neurodegenerative diseases progressively form aggregates containing both shared components (e.g., TDP-43, phosphorylated tau) and proteins specific to each disease. We investigated whether diverse neuropathies might have additional aggregation-prone proteins in common, discoverable by proteomics. Caenorhabditis elegans expressing unc-54p/Q40::YFP, a model of polyglutamine array diseases such as Huntington's, accrues aggregates in muscle 2-6days posthatch. These foci, isolated on antibody-coupled magnetic beads, were characterized by high-resolution mass spectrometry. Three Q40::YFP-associated proteins were inferred to promote aggregation and cytotoxicity, traits reduced or delayed by their RNA interference knockdown. These RNAi treatments also retarded aggregation/cytotoxicity in Alzheimer's disease models, nematodes with muscle or pan-neuronal A(1-42) expression and behavioral phenotypes. The most abundant aggregated proteins are glutamine/asparagine-rich, favoring hydrophobic interactions with other random-coil domains. A particularly potent modulator of aggregation, CRAM-1/HYPK, contributed