The protein homeostasis (proteostasis) system encompasses the cellular processes that regulate protein synthesis, folding, concentration, trafficking and degradation. In the case of intracellular proteostasis, the identity and nature of these processes have been extensively studied and are relatively well known. By contrast, the mechanisms of extracellular proteostasis are yet to be fully elucidated, although evidence is accumulating that their age-related progressive impairment might contribute to neuronal death in neurodegenerative diseases. Constitutively secreted extracellular chaperones are emerging as key players in processes that operate to protect neurons and other brain cells by neutralizing the toxicity of extracellular protein aggregates and promoting their safe clearance and disposal. Growing evidence indicates that these extracellular chaperones exert multiple effects to promote cell viability and protect neurons against pathologies arising from the misfolding and aggregation of proteins in the synaptic space and interstitial fluid. In this Review, we outline the current knowledge of the mechanisms of extracellular proteostasis linked to neurodegenerative diseases, and we examine the latest understanding of key molecules and processes that protect the brain from the pathological consequences of extracellular protein aggregation and proteotoxicity. Finally, we contemplate possible therapeutic opportunities for neurodegenerative diseases on the basis of this emerging knowledge.
Evidence is accumulating that age-related impairment of extracellular proteostasis contributes to neuronal death in neurodegenerative diseases.
Key elements implicated in the protective functioning of extracellular proteostasis are a growing family of constitutively secreted extracellular chaperones and extracellular proteases, including plasmin, which is regulated by the plasminogen activation system.
Multiple studies have already demonstrated the benefits of administering exogenous extracellular chaperones or increasing their level of expression in animal models of neurodegenerative diseases.
Strategies to manipulate elements of extracellular proteostasis have the potential to reduce excessive levels of misfolded proteins in the synaptic space and interstitial fluid and thereby to ameliorate associated disease pathologies.
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Wilson, M.R., Satapathy, S. & Vendruscolo, M. Extracellular protein homeostasis in neurodegenerative diseases. Nat Rev Neurol 19, 235–245 (2023). https://doi.org/10.1038/s41582-023-00786-2