Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy.
Dulbecco Telethon Institute, 80078 Pozzuoli, Italy.
Annu Rev Neurosci. 2016 Jul 8;39:277-95. doi: 10.1146/annurev-neuro-070815-014031. Epub 2016 Apr 18.
Recent studies of autophagic and lysosomal pathways have significantly changed our understanding of lysosomes; once thought to be simple degradative and recycling centers, lysosomes are now known to be organelles capable of influencing signal transduction, via the mammalian target of rapamycin complex 1 (mTORC1), and regulating gene expression, via transcription factor EB (TFEB) and other transcription factors. These pathways are particularly relevant to maintaining brain homeostasis, as dysfunction of the endolysosomal and autophagic pathways has been associated with common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's, and lysosomal storage disorders, a group of inherited disorders characterized by the intralysosomal buildup of partially degraded metabolites. This review focuses on the cellular biology of lysosomes and discusses the possible mechanisms by which disruption of their function contributes to neurodegeneration. We also review and discuss how targeting TFEB and lysosomes may offer innovative therapeutic approaches for treating a wide range of neurological conditions.
近年来，自噬和溶酶体途径的研究极大地改变了我们对溶酶体的认识；溶酶体曾被认为是简单的降解和回收中心，现在已知它能够通过哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）影响信号转导，并通过转录因子 EB（TFEB）和其他转录因子调节基因表达。这些途径与维持大脑内稳态特别相关，因为内溶酶体和自噬途径的功能障碍与常见的神经退行性疾病（如阿尔茨海默病、帕金森病和亨廷顿病）和溶酶体贮积症（一组以部分降解代谢物在溶酶体内蓄积为特征的遗传性疾病）有关。本文重点讨论了溶酶体的细胞生物学，并讨论了其功能障碍导致神经退行性变的可能机制。我们还回顾和讨论了靶向 TFEB 和溶酶体如何为治疗广泛的神经疾病提供创新的治疗方法。
