治愈所有罕见肾脏疾病？探索基于机制的蛋白病治疗方法。
A Rare Kidney Disease To Cure Them All? Towards Mechanism-Based Therapies for Proteinopathies.
机构信息
The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
出版信息
Trends Mol Med. 2021 Apr;27(4):394-409. doi: 10.1016/j.molmed.2020.11.008. Epub 2020 Dec 16.
Autosomal dominant tubulointerstitial kidney diseases (ADTKDs) are a group of rare genetic diseases that lead to kidney failure. Mutations in the MUC1 gene cause ADTKD-MUC1 (MUC1 kidney disease, MKD), a disorder with no available therapies. Recent studies have identified the molecular and cellular mechanisms that drive MKD disease pathogenesis. Armed with patient-derived cell lines and pluripotent stem cell (iPSC)-derived kidney organoids, it was found that MKD is a toxic proteinopathy caused by the intracellular accumulation of misfolded MUC1 protein in the early secretory pathway. We discuss the advantages of studying rare monogenic kidney diseases, describe effective patient-derived model systems, and highlight recent mechanistic insights into protein quality control that have implications for additional proteinopathies beyond rare kidney diseases.
常染色体显性遗传性肾小管间质性肾病（ADTKDs）是一组导致肾衰竭的罕见遗传疾病。MUC1 基因突变导致 ADTKD-MUC1（MUC1 肾病，MKD），目前尚无可用的治疗方法。最近的研究已经确定了驱动 MKD 疾病发病机制的分子和细胞机制。利用患者来源的细胞系和多能干细胞（iPSC）衍生的肾类器官，研究发现 MKD 是一种由早期分泌途径中错误折叠的 MUC1 蛋白在细胞内积累引起的毒性蛋白病。我们讨论了研究罕见单基因肾脏疾病的优势，描述了有效的患者来源模型系统，并强调了最近关于蛋白质质量控制的机制见解，这些见解对除罕见肾脏疾病以外的其他蛋白质病具有重要意义。
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