Foster Adriana Delice, Rea Sarah Lyn
Harry Perkins Institute of Medical Research, University of Western Australia; Perron Institute for Neurological and Translational Science, Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Western Australia, Australia; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia, Australia.
Neural Regen Res. 2020 Dec;15(12):2186-2194. doi: 10.4103/1673-5374.284977.
Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are multifaceted diseases with genotypic, pathological and clinical overlap. One such overlap is the presence of SQSTM1/p62 mutations. While traditionally mutations manifesting in the ubiquitin-associated domain of p62 were associated with Paget's disease of bone, mutations affecting all functional domains of p62 have now been identified in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients. p62 is a multifunctional protein that facilitates protein degradation through autophagy and the ubiquitin-proteasome system, and also regulates cell survival via the Nrf2 antioxidant response pathway, the nuclear factor-kappa B signaling pathway and apoptosis. Dysfunction in these signaling and protein degradation pathways have been observed in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and mutations that affect the role of p62 in these pathways may contribute to disease pathogenesis. In this review we discuss the role of p62 in these pathways, the effects of p62 mutations and the effect of mutations in the p62 modulator TANK-binding kinase 1, in relation to amyotrophic lateral sclerosis-frontotemporal lobar degeneration pathogenesis.
肌萎缩侧索硬化症和额颞叶变性是具有基因型、病理学和临床重叠的多方面疾病。其中一个重叠点是SQSTM1/p62突变的存在。虽然传统上在p62的泛素相关结构域中表现出的突变与骨Paget病相关，但现在已在肌萎缩侧索硬化症和额颞叶变性患者中鉴定出影响p62所有功能结构域的突变。p62是一种多功能蛋白，它通过自噬和泛素 - 蛋白酶体系统促进蛋白质降解，还通过Nrf2抗氧化反应途径、核因子 - κB信号通路和细胞凋亡来调节细胞存活。在肌萎缩侧索硬化症和额颞叶变性中已观察到这些信号传导和蛋白质降解途径的功能障碍，影响p62在这些途径中作用的突变可能有助于疾病的发病机制。在这篇综述中，我们讨论了p62在这些途径中的作用、p62突变的影响以及p62调节剂TANK结合激酶1中的突变对肌萎缩侧索硬化症 - 额颞叶变性发病机制的影响。
