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Pharmacologic enhancement of retromer rescues endosomal pathology induced by defects in the Alzheimer’s gene SORL1
Stem Cell Reports ( IF 5.9 ) Pub Date : 2023-11-09 , DOI: 10.1016/j.stemcr.2023.10.011
Swati Mishra 1 , Allison Knupp 1 , Chizuru Kinoshita 1 , C Andrew Williams 1 , Shannon E Rose 1 , Refugio Martinez 1 , Panos Theofilas 2 , Jessica E Young 1
Affiliation  

The SORL1 gene (SORLA) is strongly associated with risk of developing Alzheimer’s disease (AD). SORLA is a regulator of endosomal trafficking in neurons and interacts with retromer, a complex that is a “master conductor” of endosomal trafficking. Small molecules can increase retromer expression in vitro, enhancing its function. We treated hiPSC-derived cortical neurons that are either fully deficient, haploinsufficient, or that harbor one copy of SORL1 variants linked to AD with TPT-260, a retromer-enhancing molecule. We show significant increases in retromer subunit VPS26B expression. We tested whether endosomal, amyloid, and TAU pathologies were corrected. We observed that the degree of rescue by TPT-260 treatment depended on the number of copies of functional SORL1 and which SORL1 variant was expressed. Using a disease-relevant preclinical model, our work illuminates how the SORL1-retromer pathway can be therapeutically harnessed.



中文翻译:


逆转录酶的药理学增强挽救了由阿尔茨海默病基因 SORL1 缺陷诱导的内体病理



SORL1 基因 (SORLA) 与患阿尔茨海默病 (AD) 的风险密切相关。SORLA 是神经元内体运输的调节因子,并与逆转录酶相互作用,逆转录酶是一种复合物,是内体运输的“主导体”。小分子可以增加体外逆转录异体的表达 ,增强其功能。我们用逆转录酶增强分子 TPT-260 处理了 hiPSC 衍生的皮层神经元,这些神经元要么完全缺陷、单倍体不足,要么携带一个与 AD 相关的 SORL1 变体拷贝。我们显示逆转录体亚基 VPS26B 表达显著增加。我们测试了内体、淀粉样蛋白和 TAU 病理是否得到纠正。我们观察到 TPT-260 治疗的挽救程度取决于功能性 SORL1 的拷贝数和表达的 SORL1 变体。使用与疾病相关的临床前模型,我们的工作阐明了如何在治疗上利用 SORL1-逆转录酶途径。

更新日期:2023-11-09
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