Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing

Abstract

<p class="first" id="P2">Neurodegenerative disorders of ageing (NDAs) such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, Huntington’s 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 likewise compromised in NDAs: chaperone-mediated autophagy, the ubiquitin–proteasome system, extracellular clearance by proteases and extrusion into the circulation <i>via</i> the blood–brain barrier and glymphatic system. This article focuses on emerging mechanisms for enhancing neurotoxic protein clearance, a strategy that may curtail the onset and slow the progression of NDAs. </p>