From aggregate structure to disease trajectory: the role of the proteostasis network

Abstract Neurodegenerative diseases are characterized by the accumulation of a small number of misfolded proteins, yet they differ markedly in cellular vulnerability and clinical outcome. We propose that this heterogeneity arises from the interaction between two largely orthogonal variables: the structural identities of protein aggregates and the identities of the cellular proteostasis networks (PNs) that engage them. Protein aggregates exist as structurally diverse assemblies with distinct intrinsic properties. At the same time, PNs vary between cell types, disease states and ageing in their composition, capacity and plasticity. As a result, the same aggregate can be efficiently cleared in one cellular context but persist, be remodelled, or give rise to self-propagating species in another. Likewise, the same PN can be protective or harmful, depending on the aggregate it encounters. Because neither aggregates nor PNs are static, their interaction evolves over time, leading to dynamic feedback between aggregate identity and PN state that shapes disease onset, progression and clinical symptoms. This view reframes neurodegenerative disease as a failure of compatibility between specific aggregate structures and the cellular protein quality control network that processes them rather than as a uniform collapse of proteostasis, and provides a framework for understanding selective vulnerability and disease trajectories. This article is part of the Theo Murphy meeting issue ‘ProteostaSys: a systems view of proteostasis’.