中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (12): 2186-2194.doi: 10.4103/1673-5374.284977

• 综述:退行性病与再生 • 上一篇    下一篇

SQSTM1 / p62在肌萎缩性侧索硬化和额颞痴呆发病机理中的作用

  

  • 出版日期:2020-12-15 发布日期:2020-08-04

The role of sequestosome 1/p62 protein in amyotrophic lateral sclerosis and frontotemporal dementia pathogenesis

Adriana Delice Foster, Sarah Lyn Rea   

  1. 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
  • Online:2020-12-15 Published:2020-08-04
  • Contact: Sarah Lyn Rea, PhD,sarah.rea@perkins.uwa.edu.au.
  • Supported by:
    This work was supported by the NHMRC-ARC Dementia Research Development Fellowship Grant (AP1102977) and an Australian
    Government Research Training Program (RTS) Scholarship.

摘要: orcid: 0000-0002-2181-9491 (Sarah Lyn Rea)

Abstract: 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.

Key words: aggregate/inclusion body formation, amyotrophic lateral sclerosis-frontotemporal lobar degeneration, autophagy, cell signaling, mitophagy, p62/SQSTM1, protein degradation