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亨廷顿病的溶酶体质量控制的损害

Paola Rusmini¹, Francesco Mina¹, Marta Valenza²

¹Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", Dipartimento di Eccellenza 2018-2027, Università degli Studi di Milano, Milan, Italy.

Cell death & disease

|October 28, 2025

概括

亨廷顿病 (HD) 涉及突变的亨廷丁 (muHTT) 聚合物绑定TFEB/TFE3,损害 lysosome质量控制和损害神经元. 恢复TFEB/TFE3功能可能会减少muHTT聚合并改善溶酶体健康.

科学领域:

神经科学是一个神经科学.
细胞生物学细胞生物学
遗传学遗传学是一种遗传学.

背景情况:

亨廷顿病 (HD) 是一种神经退行性疾病,由亨廷丁蛋白 (muHTT) 中的多重胺 (polyQ) 扩张引起,导致蛋白质错误折叠和聚合.
这些muHTT聚合物通过隔离必要的蛋白质来破坏细胞平衡,包括调节 lysosome 功能的转录因子,如TFEB和TFE3.
溶解体对于细胞废物处理和信号传递至关重要;它们的功能障碍,特别是溶解体膜通透性 (LMP),有助于神经退行.

研究的目的:

调查转录因子TFEB和TFE3在亨廷顿病病原发生中的作用.
阐明muHTT聚合,溶酶体功能障碍和HD中的溶酶体质量控制 (LQC) 系统之间的关系.
探索HD模型中调节TFEB和TFE3活性的治疗潜力.

主要方法:

利用亨廷顿病小鼠和表达突变亨廷丁 (muHTT) 的细胞模型与多重氨酸扩展.
研究了TFEB和TFE3与muHTT聚合物和溶酶体膜通透性 (LMP) 相关的亚细胞局部化.
评估了TFEB和TFE3操纵 (沉默和过度表达) 对muHTT聚合,LGALS3水平和溶酶体动态 (溶酶体,溶酶体替代) 的影响.

主要成果:

在HD模型中,TFEB和TFE3被发现被隔离在muHTT聚合物中.
muHTT聚合与LMP和加勒-3 (LGALS3) 转移到溶酶体有关,严重程度与polyQ长度相关.
TFEB/TFE3 knockdown 加剧了 muHTT 聚合,而过度表达通过促进溶解体和溶解体替代减少了包含和 LGALS3 积累.

结论:

在muHTT聚合物中对TFEB和TFE3的隔离会损害溶酶体质量控制 (LQC) 系统,增加神经元对HD溶酶体损伤的脆弱性.
降低TFEB/TFE3的生物可用性阻止了对溶解体损伤的适当反应,导致功能障碍的溶解体的积累.
调节TFEB和TFE3为亨廷顿病提供了潜在的治疗策略,通过减轻muHTT聚合和恢复 lysosomal homeostasis.

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