Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration.
Upregulation of the ESCRT pathway and multivesicular bodies accelerates degradation of proteins associated with neurodegeneration.
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DOI：
10.1080/27694127.2023.2166722
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发表时间：
2023-01
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通讯作者：
Ron Benyair;S. Giridharan;Pilar Rivero-Ríos;Junya Hasegawa;Emily Bristow;E. Eskelinen;Merav D. Shmueli;Vered Fishbain-Yoskovitz;Y. Merbl;L. Sharkey;H. Paulson;P. Hanson;S. Patnaik;I. Al-Ramahi;J. Botas;Juan Marugan;L. Weisman
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作者：
Ron Benyair;S. Giridharan;Pilar Rivero-Ríos;Junya Hasegawa;Emily Bristow;E. Eskelinen;Merav D. Shmueli;Vered Fishbain-Yoskovitz;Y. Merbl;L. Sharkey;H. Paulson;P. Hanson;S. Patnaik;I. Al-Ramahi;J. Botas;Juan Marugan;L. Weisman
许多神经退行性疾病，包括亨廷顿氏病（HD）和阿尔茨海默氏病（AD），由于聚集倾向蛋白的积累而发生，这导致神经元死亡。在动物和细胞模型中的研究表明，降低这些蛋白质的水平可以减轻疾病表型。我们先前报道了一种小分子，NCT-504，它降低了患者成纤维细胞以及HdhQ 111突变小鼠的小鼠纹状体和皮质神经元中突变亨廷顿蛋白（mHTT）的细胞水平。在这里，我们表明NCT-504具有更广泛的潜力，此外还降低了Tau的水平，Tau是一种与阿尔茨海默病以及其他Tau病相关的蛋白质。我们发现在未处理的细胞中，Tau和mHTT通过自噬降解。值得注意的是，用NCT-504处理将这些蛋白质转移到多泡体（MVB）和ESCRT途径。具体地，NCT-504引起包括MVB在内的内溶酶体细胞器的增殖，以及mHTT和Tau与内体和MVB的增强的缔合。重要的是，ESCRT途径中晚期作用的蛋白质的消耗可以阻止NCT-504依赖性的Tau降解。此外，NCT-504介导的Tau降解发生在Atg 7耗尽的细胞中，这表明该途径不依赖于典型的自噬。总之，这些研究表明，通过ESCRT依赖性MVB途径的交通量上调可能为神经退行性疾病提供治疗方法。
Many neurodegenerative diseases, including Huntington's disease (HD) and Alzheimer's disease (AD), occur due to an accumulation of aggregation-prone proteins, which results in neuronal death. Studies in animal and cell models show that reducing the levels of these proteins mitigates disease phenotypes. We previously reported a small molecule, NCT-504, which reduces cellular levels of mutant huntingtin (mHTT) in patient fibroblasts as well as mouse striatal and cortical neurons from an HdhQ111 mutant mouse. Here, we show that NCT-504 has a broader potential, and in addition reduces levels of Tau, a protein associated with Alzheimer's disease, as well as other tauopathies. We find that in untreated cells, Tau and mHTT are degraded via autophagy. Notably, treatment with NCT-504 diverts these proteins to multivesicular bodies (MVB) and the ESCRT pathway. Specifically, NCT-504 causes a proliferation of endolysosomal organelles including MVB, and an enhanced association of mHTT and Tau with endosomes and MVB. Importantly, depletion of proteins that act late in the ESCRT pathway blocked NCT-504 dependent degradation of Tau. Moreover, NCT-504-mediated degradation of Tau occurred in cells where Atg7 is depleted, which indicates that this pathway is independent of canonical autophagy. Together, these studies reveal that upregulation of traffic through an ESCRT-dependent MVB pathway may provide a therapeutic approach for neurodegenerative diseases.