The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, VIC, 3052, Australia.
Department of Medical Biology, University of Melbourne, Royal Parade, Melbourne, VIC, 3052, Australia.
Cell Death Differ. 2021 Feb;28(2):570-590. doi: 10.1038/s41418-020-00706-7. Epub 2021 Jan 7.
Neurodegenerative diseases are characterised by progressive damage to the nervous system including the selective loss of vulnerable populations of neurons leading to motor symptoms and cognitive decline. Despite millions of people being affected worldwide, there are still no drugs that block the neurodegenerative process to stop or slow disease progression. Neuronal death in these diseases is often linked to the misfolded proteins that aggregate within the brain (proteinopathies) as a result of disease-related gene mutations or abnormal protein homoeostasis. There are two major degradation pathways to rid a cell of unwanted or misfolded proteins to prevent their accumulation and to maintain the health of a cell: the ubiquitin-proteasome system and the autophagy-lysosomal pathway. Both of these degradative pathways depend on the modification of targets with ubiquitin. Aging is the primary risk factor of most neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. With aging there is a general reduction in proteasomal degradation and autophagy, and a consequent increase of potentially neurotoxic protein aggregates of β-amyloid, tau, α-synuclein, SOD1 and TDP-43. An often over-looked yet major component of these aggregates is ubiquitin, implicating these protein aggregates as either an adaptive response to toxic misfolded proteins or as evidence of dysregulated ubiquitin-mediated degradation driving toxic aggregation. In addition, non-degradative ubiquitin signalling is critical for homoeostatic mechanisms fundamental for neuronal function and survival, including mitochondrial homoeostasis, receptor trafficking and DNA damage responses, whilst also playing a role in inflammatory processes. This review will discuss the current understanding of the role of ubiquitin-dependent processes in the progressive loss of neurons and the emergence of ubiquitin signalling as a target for the development of much needed new drugs to treat neurodegenerative disease.
神经退行性疾病的特征是神经系统进行性损伤，包括易损神经元群体的选择性丧失，导致运动症状和认知能力下降。尽管全世界有数以百万计的人受到影响，但仍然没有药物能够阻止神经退行性过程，从而阻止或减缓疾病的进展。这些疾病中的神经元死亡通常与脑内错误折叠的蛋白质聚集有关（蛋白病），这是由于与疾病相关的基因突变或异常蛋白质同源性。有两种主要的降解途径可以清除细胞中不需要的或错误折叠的蛋白质，以防止它们的积累并维持细胞的健康：泛素-蛋白酶体系统和自噬溶酶体途径。这两种降解途径都依赖于泛素对靶标的修饰。衰老 是大多数神经退行性疾病的主要危险因素，包括阿尔茨海默病、帕金森病和肌萎缩侧索硬化症。随着年龄的增长，蛋白酶体降解和自噬普遍减少，β-淀粉样蛋白、tau、α-突触核蛋白、SOD1 和 TDP-43 等潜在神经毒性蛋白聚集体的含量相应增加。这些聚集体中经常被忽视但却是主要成分的是泛素，这表明这些蛋白聚集体要么是对有毒错误折叠蛋白的适应性反应，要么是失调的泛素介导的降解驱动毒性聚集的证据。此外，非降解泛素信号对于神经元功能和存活的基本同源机制至关重要，包括线粒体同源性、受体运输和 DNA 损伤反应，同时也在炎症过程中发挥作用。本文综述了泛素依赖性过程在神经元进行性丧失中的作用的现有认识，以及泛素信号作为开发治疗神经退行性疾病所需的新型药物的靶点的出现。
