Proteostasis, disease and the ageing neuron: Compartmental complexity in non-renewing cells

Proteostasis, the maintenance of protein homeostasis, is a critical cellular process for neuronal health that declines with age, contributing to neurodegenerative disease. This review examines the molecular architecture of the proteostasis network, how this is disrupted in ageing neurons, and its impact on neuronal function. We discuss unique challenges posed by the complexity arising from distinct neuronal compartments with distinct functions, as well as neurons’ high energy demands, and post-mitotic status. We next detail how proteostasis mechanisms differ across neuronal compartments and neural subtypes, and how these differences influence susceptibility to stress and disease. Finally, we explore how these differences shape selective vulnerability in neurodegenerative diseases. By integrating recent transcriptomic and proteomic insights, this review highlights the need for compartment- and cell-type-specific approaches to mitigate proteostasis collapse in the ageing brain. • Ageing neurons show compartment-specific collapse of proteostasis networks • Axons and dendrites differ in proteostasis capacity and stress susceptibility • High ATP demand and post-mitotic state exacerbate proteostasis decline in neurons • Transcriptomic and proteomic data reveal subtype-specific proteostasis signatures • Targeting compartmental proteostasis may mitigate selective neurodegeneration