Department of Laboratory Sciences, School of Paramedicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Department of Clinical Biochemistry and Molecular Biology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Biofactors. 2017 Nov;43(6):737-759. doi: 10.1002/biof.1264. Epub 2016 Feb 22.
Protein misfolding and inclusion body formations are common events in neurodegenerative diseases characterized by deposition of misfolded proteins inside or outside of neurons, and are commonly referred to as "protein misfolding neurodegenerative diseases" (PMNDs). These phenotypically diverse but biochemically similar aggregates suggest a highly conserved molecular mechanism of pathogenesis. These challenges are magnified by presence of mutations that render individual proteins subject to misfolding and/or aggregation. Cell proteostasis network and molecular chaperoning are maintaining cell proteome to preserve the protein folding, refolding, oligomerization, or disaggregation, and play formidable tasks to maintain the health of organism in the face of developmental changes, environmental insults, and rigors of aging. Maintenance of cell proteome requires the orchestration of major pathways of the cellular proteostasis network (heat shock response (HSR) in the cytosol and the unfolded protein response (UPR) in the endoplasmic reticulum). Proteostasis responses culminate in transcriptional and post-transcriptional programs that up-regulate the homeostatic mechanisms. Proteostasis is strongly influenced by the general properties of individual proteins for folding, misfolding, and aggregation. We examine a growing body of evidence establishing that when cellular proteostasis goes awry, it can be reestablished by deliberate chemical and biological interventions. We first try to introduce some new chemical approaches to prevent the misfolding or aggregation of specific proteins via direct binding interactions. We then start with approaches that employ chemicals or biological agents to enhance the general capacity of the proteostasis network. We finish with evidence that synergy is achieved with the combination of mechanistically distinct approaches to reestablish organ proteostasis. © 2016 BioFactors, 43(6):737-759, 2017.
蛋白质错误折叠和包含体形成是神经退行性疾病的常见事件，其特征是错误折叠的蛋白质在神经元内外沉积，通常被称为“蛋白质错误折叠神经退行性疾病”（PMNDs）。这些表型多样但生化相似的聚集物表明存在高度保守的发病机制。存在使个别蛋白质易于错误折叠和/或聚集的突变，这增加了这些挑战。细胞蛋白质稳态网络和分子伴侣在维持细胞蛋白质组方面发挥着重要作用，以保持蛋白质折叠、重折叠、寡聚化或解聚，并在面对发育变化、环境损伤和衰老的严峻考验时，发挥着维持生物体健康的艰巨任务。细胞蛋白质组的维持需要细胞蛋白质稳态网络的主要途径（细胞质中的热休克反应（HSR）和内质网中的未折叠蛋白反应（UPR））的协调。蛋白质稳态反应最终导致转录和转录后程序上调稳态机制。蛋白质稳态受单个蛋白质折叠、错误折叠和聚集的一般特性强烈影响。我们研究了越来越多的证据，这些证据确立了当细胞蛋白质稳态出现问题时，可以通过故意的化学和生物学干预来重新建立。我们首先尝试引入一些新的化学方法，通过直接结合相互作用来防止特定蛋白质的错误折叠或聚集。然后，我们从采用化学物质或生物制剂来增强蛋白质稳态网络的一般能力的方法开始。最后，有证据表明，通过采用机制上不同的方法相结合，可以实现器官蛋白质稳态的协同作用。©2016 生物因素，43（6）：737-759，2017 年。
