Starting at the beginning: endoplasmic reticulum proteostasis and systemic amyloid disease.
Starting at the beginning: endoplasmic reticulum proteostasis and systemic amyloid disease.
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DOI：
10.1042/bcj20190312
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发表时间：
2020-05-15
期刊：
影响因子：
--
通讯作者：
Wiseman, R Luke
中科院分区：
文献类型：
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作者：
Romine, Isabelle C;Wiseman, R Luke
系统性淀粉样蛋白疾病的特征是淀粉样蛋白作为毒性低聚物和淀粉样原纤维沉积在远离蛋白质合成部位的组织上。传统上，这些疾病被认为是周围靶组织的疾病，聚集物沉积在那里，并观察到毒性。然而，最近的证据强调了在合成和分泌淀粉样蛋白的组织（如肝脏）中内质网（ER）蛋白平衡途径在这些疾病的发病机制中的重要作用。在这里，我们描述了内质网蛋白停滞的病理意义及其对淀粉样蛋白毒性细胞外聚集的调节，涉及系统性淀粉样蛋白病的发病机制。此外，我们讨论了靶向内质网蛋白静止的治疗潜力，以减少淀粉样蛋白的分泌和毒性聚集，以减轻参与系统性淀粉样疾病发生和进展的外周淀粉样蛋白相关毒性。
Systemic amyloid diseases are characterized by the deposition of an amyloidogenic protein as toxic oligomers and amyloid fibrils on tissues distal from the site of protein synthesis. Traditionally, these diseases have been viewed as disorders of peripheral target tissues where aggregates are deposited, and toxicity is observed. However, recent evidence highlights an important role for endoplasmic reticulum (ER) proteostasis pathways within tissues synthesizing and secreting amyloidogenic proteins, such as the liver, in the pathogenesis of these disorders. Here, we describe the pathologic implications of ER proteostasis and its regulation on the toxic extracellular aggregation of amyloidogenic proteins implicated in systemic amyloid disease pathogenesis. Furthermore, we discuss the therapeutic potential for targeting ER proteostasis to reduce the secretion and toxic aggregation of amyloidogenic proteins to mitigate peripheral amyloid-associated toxicity involved in the onset and progression of systemic amyloid diseases.