Loss of Proteostasis

Endogenous and exogenous stress causes the unfolding of proteins (or impairs proper folding during protein synthesis). Unfolded proteins are usually refolded by heat-shock proteins (HSP) or targeted to destruction by the ubiquitin-proteasome or lysosomal (autophagic) pathways. The autophagic pathways include recognition of unfolded proteins by the chaperone Hsc70 and their subsequent import into lysosomes (chaperone-mediated autophagy) or sequestration of damaged proteins and organelles in autophagosomes that later fuse with lysosomes (macroautophagy). Failure to refold or degrade unfolded proteins can lead to their accumulation and aggregation, resulting in proteotoxic effects.

Loss of Proteostasis is one of the primary hallmarks of aging, signifying the decline in the cell's ability to regulate protein balance. Proteostasis encompasses all aspects of protein metabolism, including the synthesis, folding, trafficking, and degradation of proteins. Efficient proteostasis is vital for maintaining cellular function and homeostasis, as proteins are integral components of all cellular processes. However, as organisms age, the proteostasis network becomes less efficient, leading to the accumulation of damaged and misfolded proteins, which can form toxic aggregates and disrupt cellular functions.

The Proteostasis Network

The proteostasis network includes several key mechanisms and pathways:

• Protein Synthesis: Ribosomes are responsible for translating mRNA into polypeptide chains, which must then fold into functional three-dimensional structures.
• Molecular Chaperones: These proteins assist in the proper folding of other proteins, preventing misfolding and aggregation.
• Protein Folding Mechanisms: Proper folding is crucial for protein function. Misfolded proteins can lead to the formation of toxic aggregates.
• Protein Degradation Systems: Two main systems, the ubiquitin-proteasome system and the autophagy-lysosome pathway, are responsible for degrading and recycling damaged or unnecessary proteins.
• Protein Trafficking: Proteins must often be transported to specific locations within or outside the cell to function correctly.

Implications of Loss of Proteostasis

The failure to maintain proteostasis has profound implications:

• Age-related Diseases: Many neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's disease, are associated with the accumulation of misfolded protein aggregates, a direct consequence of impaired proteostasis.
• Cellular Stress Response: Impaired proteostasis leads to cellular stress and the activation of various stress response pathways, which can have additional deleterious effects on cell function.
• Inflammation: The accumulation of misfolded proteins can trigger inflammatory responses, contributing to tissue damage and age-related pathologies.
• Reduced Cellular Function: Accumulation of damaged proteins can disrupt cellular functions, leading to reduced cellular performance and viability.

Molecular Chaperones and Heat Shock Proteins

Molecular chaperones and heat shock proteins play a critical role in maintaining proteostasis. They recognize and bind to misfolded or unfolded proteins, preventing their aggregation and assisting in proper refolding or directing them to degradation pathways. These proteins are particularly important during cellular stress, where the risk of protein misfolding is increased. However, the expression and functionality of chaperones decline with age, contributing to the loss of proteostasis.

The Role of Autophagy in Proteostasis

Autophagy, specifically macroautophagy, is a cellular degradation pathway that plays a significant role in removing damaged organelles and protein aggregates. During autophagy, cellular components are sequestered into autophagosomes, which then fuse with lysosomes for degradation. Impaired autophagy is a common feature in aged cells and is associated with the accumulation of protein aggregates and dysfunctional organelles.

The Ubiquitin-Proteasome System

The ubiquitin-proteasome system is another crucial component of the proteostasis network, responsible for the targeted degradation of proteins. Proteins marked for degradation are tagged with ubiquitin molecules and directed to the proteasome, where they are broken down into amino acids. Dysregulation or decline in the efficiency of the ubiquitin-proteasome system is observed in aging and is associated with the accumulation of damaged or misfolded proteins.

Therapeutic Interventions

Given the central role of proteostasis in aging and disease, strategies to enhance proteostasis are of considerable interest. Potential approaches include boosting the expression or activity of molecular chaperones, enhancing autophagy, and improving the efficiency of the ubiquitin-proteasome system. Such interventions could help prevent or mitigate the effects of protein aggregation diseases and extend healthy lifespan.

See Also

• Hallmarks of Aging
• Wikipedia - Proteostasis § Proteostasis and aging