Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases.
Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases.
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DOI：
10.3390/ijms232415457
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发表时间：
2022-12-07
影响因子：
5.6
通讯作者：
Ayyadevara, Srinivas
中科院分区：
文献类型：
--
作者：
Ganne, Akshatha;Balasubramaniam, Meenakshisundaram;Mainali, Nirjal;Atluri, Paavan;Reis, Robert J. Shmookler J.;Ayyadevara, Srinivas
哺乳动物14-3-3家族包括7种本质上非结构化的、进化上保守的蛋白质，其结合>200种蛋白质靶标，从而调节细胞信号传导途径。脑脊液中14-3-3蛋白的存在提供了与阿尔茨海默病（AD）、克雅氏病（CJD）、海绵状脑炎、脑癌和中风相关的神经元损伤的敏感且特异的生物标志物。我们观察到14-3-3旁系同源物G、S和Z在诊断AD的人脑聚集体中的显著富集。我们使用聚集体内交联来鉴定14-3-3相互作用伴侣，相对于对照，所有这些都显著富集在AD脑聚集体中。我们通过计算机模拟筛选了FDA批准的药物，以寻找可以靶向14-3-3G/己糖激酶界面的结构，这是一种对聚集体和AD特异性的相互作用。C.线虫只有两个14-3-3直系同源物，它们结合不同的蛋白质，包括foxo-16（一种FOXO转录因子）和SIR-2.1（一种营养和压力传感器），影响寿命。在C. elegans模型的神经变性相关聚集和AD样淀粉样变性的人神经母细胞瘤细胞培养模型。几种药物在所有评估和挽救C. elegans AD样神经病变模型，表明14-3-3蛋白有助于聚集的积累，并支持靶向14-3-3蛋白复合物与其伴侣的药物的发展。
The mammalian 14-3-3 family comprises seven intrinsically unstructured, evolutionarily conserved proteins that bind >200 protein targets, thereby modulating cell-signaling pathways. The presence of 14-3-3 proteins in cerebrospinal fluid provides a sensitive and specific biomarker of neuronal damage associated with Alzheimer’s disease (AD), Creutzfeldt–Jakob disease (CJD), spongiform encephalitis, brain cancers, and stroke. We observed significant enrichment of 14-3-3 paralogs G, S, and Z in human brain aggregates diagnostic of AD. We used intra-aggregate crosslinking to identify 14-3-3 interaction partners, all of which were significantly enriched in AD brain aggregates relative to controls. We screened FDA-approved drugs in silico for structures that could target the 14-3-3G/hexokinase interface, an interaction specific to aggregates and AD. C. elegans possesses only two 14-3-3 orthologs, which bind diverse proteins including DAF-16 (a FOXO transcription factor) and SIR-2.1 (a sensor of nutrients and stress), influencing lifespan. Top drug candidates were tested in C. elegans models of neurodegeneration-associated aggregation and in a human neuroblastoma cell-culture model of AD-like amyloidosis. Several drugs opposed aggregation in all models assessed and rescued behavioral deficits in C. elegans AD-like neuropathy models, suggesting that 14-3-3 proteins are instrumental in aggregate accrual and supporting the advancement of drugs targeting 14-3-3 protein complexes with their partners.
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DOI：
10.1161/hypertensionaha.115.06849
发表时间：
2016-05
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Ayyadevara S;Mercanti F;Wang X;Mackintosh SG;Tackett AJ;Prayaga SV;Romeo F;Shmookler Reis RJ;Mehta JL
通讯作者：
Mehta JL
影响因子：
5.2
作者：
Ayyadevara, Srinivas;Balasubramaniam, Meenakshisundaram;Dennis, Richard A.
通讯作者：
Dennis, Richard A.
影响因子：
7.8
作者：
Ayyadevara, Srinivas;Balasubramaniam, Meenakshisundaram;Reis, Robert Shmookler
通讯作者：
Reis, Robert Shmookler
影响因子：
4.8
作者：
Kakraba, Samuel;Ayyadevara, Srinivas;Reis, Robert J. Shmookler
通讯作者：
Reis, Robert J. Shmookler
影响因子：
6
作者：
Pozuelo-Rubio M
通讯作者：
Pozuelo-Rubio M