Protein Aggregation - Causes

Causes

Protein aggregation can occur due to a variety of causes. Individuals may have mutations that encode for proteins that are particularly sensitive to misfolding and aggregation. Alternatively, disruption of the pathways to refold proteins (chaperones) or to degrade misfolded proteins (the ubiquitin-proteasome pathway) may lead to protein aggregation. As many of the diseases associated with protein aggregation increase in frequency with age, it seems that cells lose the ability to clear misfolded proteins and aggregates over time. Several new studies suggests that protein aggregation is a second line of the cellular reaction to an imbalanced protein homeostasis rather than a harmful, random process. A groundbreaking study showed that sequestration of misfolded, aggregation-prone proteins into inclusion sites is an active organized cellular process, that depends on quality control components, such as HSPs and co-chaperones. Moreover, it was shown that eukaryotic cells have the ability to sort misfolded proteins in to two quality control compartments: 1. The JUNQ (JUxta Nuclear Quality control compartment). 2. The IPOD (Insoluble Protein Deposit). The partition into two quality control compartments is due to the different handling and processing of the different kinds of misfolded aggregative proteins: The IPOD serves as a sequestration site for non-ubiquitinated terminally aggregated proteins, such as the huntingtin protein. Under stress conditions, such as heat, when the cellular quality control machinery is saturated, ubiquitinated proteins are sorted to the JUNQ compartment, where they are eventually degraded. Thus, aggregation is a regulated, controlled process.