Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic–lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin–proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood–brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.

鉴于老年痴呆症的高患病率和不良治疗，其老年性神经退行性疾病（NDA），例如阿尔茨海默氏病，帕金森氏病，额颞痴呆，亨廷顿病和肌萎缩性侧索硬化症，构成了重大的社会经济挑战。由于存在错误折叠和聚集的蛋白质，这些蛋白质会失去其生理作用并获得神经毒性，因此通常被称为“蛋白质病”。神经毒性蛋白的寡聚体形式的积累和扩散的根本原因之一是自噬-溶酶体网络的清除不足。NDAs还破坏了其他几种清除途径：伴侣介导的自噬，泛素-蛋白酶体系统，蛋白酶的细胞外清除以及通过血脑屏障和淋巴系统挤出进入循环系统。