Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes,Chemical Reviews

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Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes
Chemical Reviews ( IF 51.4 ) Pub Date : 2021-01-11 , DOI: 10.1021/acs.chemrev.0c00981
Danilo Milardi ₁ , Ehud Gazit ₂ , Sheena E Radford ₃ , Yong Xu ₃ , Rodrigo U Gallardo ₃ , Amedeo Caflisch ₄ , Gunilla T Westermark ₅ , Per Westermark ₆ , Carmelo La Rosa ₇ , Ayyalusamy Ramamoorthy ₈

Affiliation

The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures and aggregation pathways of this hormone. Recent studies have reported on the importance of early oligomeric intermediates, the many roles of their interactions with lipid membrane, pH, insulin, and zinc on the mechanism of aggregation of hIAPP. The challenges posed by the transient nature of amyloid oligomers, their structural heterogeneity, and the complex nature of their interaction with lipid membranes have resulted in the development of a wide range of biophysical and chemical approaches to characterize the aggregation process. While the cellular processes and factors activating hIAPP-mediated cytotoxicity are still not clear, it has recently been suggested that its impaired turnover and cellular processing by proteasome and autophagy may contribute significantly toward toxic hIAPP accumulation and, eventually, β-cell death. Therefore, studies focusing on the restoration of hIAPP proteostasis may represent a promising arena for the design of effective therapies. In this review we discuss the current knowledge of the structures and pathology associated with hIAPP self-assembly and point out the opportunities for therapy that a detailed biochemical, biophysical, and cellular understanding of its aggregation may unveil.

中文翻译：

胰岛淀粉样多肽的蛋白质稳态：II 型糖尿病危险因素和保护策略的分子视角

糖尿病患者中 hIAPP 积累与 β 细胞死亡之间可能存在的联系激发了许多针对淀粉样蛋白结构和该激素聚集途径的研究。最近的研究报道了早期寡聚中间体的重要性，以及它们与脂质膜、pH、胰岛素和锌的相互作用对 hIAPP 聚集机制的许多作用。淀粉样蛋白寡聚体的瞬时性质、其结构异质性以及其与脂质膜相互作用的复杂性质所带来的挑战导致了广泛的生物物理和化学方法的发展来表征聚集过程。虽然激活 hIAPP 介导的细胞毒性的细胞过程和因素仍不清楚，最近有人提出，蛋白酶体和自噬的周转和细胞加工受损可能会显着导致有毒的 hIAPP 积累，并最终导致 β 细胞死亡。因此，专注于恢复 hIAPP 蛋白质稳态的研究可能为设计有效疗法提供了一个有前景的领域。在这篇综述中，我们讨论了与 hIAPP 自组装相关的结构和病理学的当前知识，并指出了对其聚集的详细生化、生物物理和细胞理解可能揭示的治疗机会。专注于恢复 hIAPP 蛋白质稳态的研究可能为设计有效疗法提供了一个有前景的领域。在这篇综述中，我们讨论了与 hIAPP 自组装相关的结构和病理学的当前知识，并指出了对其聚集的详细生化、生物物理和细胞理解可能揭示的治疗机会。专注于恢复 hIAPP 蛋白质稳态的研究可能为设计有效疗法提供了一个有前景的领域。在这篇综述中，我们讨论了与 hIAPP 自组装相关的结构和病理学的当前知识，并指出了对其聚集的详细生化、生物物理和细胞理解可能揭示的治疗机会。

更新日期：2021-02-10

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