Ageing is a major risk factor for the development of many diseases, prominently including neurodegenerative disorders such as Alzheimer disease and Parkinson disease. A hallmark of many age-related diseases is the dysfunction in protein homeostasis (proteostasis), leading to the accumulation of protein aggregates. In healthy cells, a complex proteostasis network, comprising molecular chaperones and proteolytic machineries and their regulators, operates to ensure the maintenance of proteostasis. These factors coordinate protein synthesis with polypeptide folding, the conservation of protein conformation and protein degradation. However, sustaining proteome balance is a challenging task in the face of various external and endogenous stresses that accumulate during ageing. These stresses lead to the decline of proteostasis network capacity and proteome integrity. The resulting accumulation of misfolded and aggregated proteins affects, in particular, postmitotic cell types such as neurons, manifesting in disease. Recent analyses of proteome-wide changes that occur during ageing inform strategies to improve proteostasis. The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan.
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The authors thank D. Balchin, D. Broch-Trentini, G. Jayaraj and C. Klaips for critically reading the manuscript. Work in the authors’ laboratory is supported by the European Commission under FP7 GA ERC-2012-SyG_318987–ToPAG and the Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the Munich Cluster for Systems Neurology.
- Intrinsically disordered regions
Regions of a protein that lack stable, well-defined tertiary structure; often functionally relevant in interactions with partner proteins.
- Tail-anchored proteins
Membrane proteins that are post-translationally inserted into the membrane. They can contain a transmembrane sequence near the carboxy terminus.
- E3 ubiquitin ligase
An enzyme that mediates the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to a protein substrate.
- E2 ubiquitin-conjugating enzyme
An enzyme that catalyses the second step in the enzymatic cascade for the transfer of ubiquitin to protein substrates.
Immature red blood cells.
A factor that assists or regulates the function of a molecular chaperone; some co-chaperones also have chaperone activity in binding non-native proteins.
- Chaperone-assisted selective autophagy
A degradation pathway of chaperone-bound proteins in lysosomes.
- Chaperone-mediated autophagy
A chaperone-dependent degradation pathway of soluble cytosolic proteins that involves translocation of the substrate protein across the lysosomal membrane.
- Endosomal microautophagy
Degradation of cytosolic proteins by late endosomes and/or multivesicular bodies.
A fibrillar aggregate, composed of polypeptides forming a cross-β structure, that has defined tinctorial (dye-binding) properties.
- Low-complexity domains
Sequences of amino acids with little diversity that are often intrinsically unstructured.
- Polyglutamine expansion
Pathogenic elongation of a polyglutamine stretch in a protein caused by an increased number of CAG trinucleotide repeats; described in a group of unrelated genes.
A class of molecular chaperones forming large, double-ring complexes that transiently enclose a substrate protein for folding (examples include HSP60 in mitochondria and TRiC in the eukaryotic cytosol).
- BRICHOS domain
A domain found in several proteins associated with dementia, respiratory distress and cancer, including BRI2, chondromodulin I and surfactant protein C. BRICHOS domains have intramolecular chaperone-like activities and inhibit misfolding and aggregation.
An adaptive response of an organism or biological system towards a low dose of a toxic agent or physical conditions (for example, reactive oxygen radicals or thermal stress) that preconditions the organism to tolerate a higher dose of the same toxic agent.
- Critical concentration
The concentration up to which a protein remains soluble; exceeding this concentration results in insolubility and aggregation.
- Unfolded protein response
(UPR). A cellular stress response pathway that serves to increase the protein-folding capacity of the endoplasmic reticulum or the mitochondria.
- Integrated stress response
A conserved signalling pathway that responds to a variety of cellular conditions and attenuates protein translation via phosphorylation of translation initiation factor 2α (eIF2α).
A tetrameric transport protein that binds to the thyroid hormone thyroxin and retinol-binding protein. Mutant forms dissociate into subunits and aggregate, resulting in transthyretin amyloidosis.