Big versus small: The impact of aggregate size in disease.
Big versus small: The impact of aggregate size in disease.
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DOI：
10.1002/pro.4686
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发表时间：
2023-07
期刊：
影响因子：
8
通讯作者：
Dokholyan, Nikolay V.
中科院分区：
文献类型：
--
作者：
Hnath, Brianna;Chen, Jiaxing;Reynolds, Joshua;Choi, Esther;Wang, Jian;Zhang, Dongyan;Sha, Congzhou M.;Dokholyan, Nikolay V.
关键词：
蛋白质聚集导致一系列不同大小的可溶性低聚物和较大的不溶性原纤维。由于不溶性原纤维在组织样品和疾病模型中的普遍存在，其最初被认为在神经退行性疾病中引起神经元细胞死亡。尽管最近的研究证明了与可溶性低聚物相关的毒性，但许多治疗策略仍然关注原纤维或将所有类型的聚集体视为一组。寡聚体和原纤维需要不同的建模和治疗策略，靶向毒性物质对于成功的研究和治疗开发至关重要。在这里，我们回顾了不同大小的聚集体在疾病中的作用，以及导致聚集的因素（突变，金属，翻译后修饰和脂质相互作用）如何促进寡聚体而不是原纤维。我们回顾了两种不同的计算建模策略（分子动力学和动力学建模），以及它们是如何被用来模拟低聚物和原纤维。最后，我们概述了目前的治疗策略，针对聚集蛋白质和他们的优势和劣势，针对寡聚体与原纤维。总之，我们的目标是强调区分寡聚体和原纤维之间的差异，并确定哪些物种是有毒的建模和创建治疗疾病中的蛋白质聚集的重要性。
Protein aggregation results in an array of different size soluble oligomers and larger insoluble fibrils. Insoluble fibrils were originally thought to cause neuronal cell deaths in neurodegenerative diseases due to their prevalence in tissue samples and disease models. Despite recent studies demonstrating the toxicity associated with soluble oligomers, many therapeutic strategies still focus on fibrils or consider all types of aggregates as one group. Oligomers and fibrils require different modeling and therapeutic strategies, targeting the toxic species is crucial for successful study and therapeutic development. Here, we review the role of different‐size aggregates in disease, and how factors contributing to aggregation (mutations, metals, post‐translational modifications, and lipid interactions) may promote oligomers opposed to fibrils. We review two different computational modeling strategies (molecular dynamics and kinetic modeling) and how they are used to model both oligomers and fibrils. Finally, we outline the current therapeutic strategies targeting aggregating proteins and their strengths and weaknesses for targeting oligomers versus fibrils. Altogether, we aim to highlight the importance of distinguishing the difference between oligomers and fibrils and determining which species is toxic when modeling and creating therapeutics for protein aggregation in disease.
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DOI：
10.1016/j.bbrc.2009.11.080
发表时间：
2010-01-01
影响因子：
3.1
作者：
Hillmer, Andreas S.;Putcha, Preeti;Levin, Johannes;Hoegen, Tobias;Hyman, Bradley T.;Kretzschmar, Hans;McLean, Pamela J.;Giese, Armin
通讯作者：
Giese, Armin
DOI：
10.3390/molecules27031021
发表时间：
2022-02-02
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Bhowmick DC;Kudaibergenova Z;Burnett L;Jeremic AM
通讯作者：
Jeremic AM
DOI：
10.1124/jpet.112.192138
发表时间：
2012-09-01
影响因子：
3.5
作者：
Johri, Ashu;Beal, M. Flint
通讯作者：
Beal, M. Flint
影响因子：
--
作者：
Auer, Stefan;Dobson, Christopher M.;Vendruscolo, Michele
通讯作者：
Vendruscolo, Michele
影响因子：
2.9
作者：
Barrett, Paul J.;Greenamyre, J. Timothy
通讯作者：
Greenamyre, J. Timothy