Ubiquitin signatures on aggregating proteins in neurodegeneration.

The aberrant accumulation of misfolded proteins marked by cellular dysfunction and progressive neuronal loss is the hallmark of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. This review examines the pivotal role of ubiquitin modifications in altering the fate of aggregation-prone proteins such as tau, α-synuclein, mutant huntingtin, TAR DNA-binding protein 43 and superoxide dismutase 1. The ubiquitin signatures identified by their linkage types, chain architectures and site specificities emerge as a complex regulatory language that influences the clearance, aggregation or cellular propagation of these aggregating proteins. The dysregulation of other components of the ubiquitin association pathways, such as impaired E3 ligases and deubiquitinases, also contributes to the inefficient protein disposal and disease progression. Understanding how ubiquitin signatures alter the spatiotemporal dynamics of aggregating proteins is critical for advancing our knowledge of disease biology. Here, we focus on the role of ubiquitin modifications and their associated regulators affecting protein fate and neurotoxicity, and highlight the current therapeutic strategies targeting the degradation of aggregating proteins to uncover potential avenues for treating neurodegenerative diseases.