Aggresome

In eukaryotic cells, an aggresome refers to an aggregation of misfolded proteins in the cell, formed when the protein degradation system of the cell is overwhelmed. Aggresome formation is a highly regulated process that possibly serves to organize misfolded proteins into a single location.

Correct folding requires proteins to assume one particular structure from a constellation of possible but incorrect conformations. The failure of polypeptides to adopt their proper structure is a major threat to cell function and viability. Consequently, elaborate systems have evolved to protect cells from the deleterious effects of misfolded proteins.

Upon synthesis, proteins are in their linear and non-functional form, called a nascent protein. They must undergo co-translational folding as quickly as possible in order to become a functional, three-dimensional structure. Normally folded proteins are referred to as being in their native structure. In this state, they have undergone a hydrophobic collapse process, indicated by outward-facing hydrophilic components and inward-facing hydrophobic components.

The solubility of proteins is an important biochemical aspect of protein folding as it has been shown to affect the formation of protein aggregates. Contrary to native structures, a misfolded protein will often have outward-facing hydrophobic regions which acts as an attractant to other insoluble proteins. There are some chaperones which identify aggregates by recognizing their hydrophobic region. These chaperone may work as solubilizers.

Cells mainly deploy three mechanisms to counteract misfolded proteins: up-regulating chaperones to assist protein refolding, proteolytic degradation of the misfolded/damaged proteins involving ubiquitin–proteasome and autophagy–lysosome systems, and formation of detergent-insoluble aggresomes by transporting the misfolded proteins along microtubules to a region near the nucleus. Intracellular deposition of misfolded protein aggregates into ubiquitin-rich cytoplasmic inclusions is linked to the pathogenesis of many diseases. Functional blockade of either degradative system leads to an enhanced aggresome formation. Why these aggregates form despite the existence of cellular machinery to recognize and degrade misfolded protein, and how they are delivered to cytoplasmic inclusions, are not known.

Aggresome formation is accompanied by redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks the formation of aggresomes. Similarly, inhibition of proteasome function also prevents the degradation of unassembled presenilin-1 (PSE₁) molecules leading to their aggregation and deposition in aggresomes. Aggresome formation is a general response of cells which occurs when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins.

Typically, an aggresome forms in response to a cellular stress which generates a large amount of misfolded or partially denatured protein: hyperthermia, overexpression of an insoluble or mutant protein, etc. The formation of the aggresome is largely believed to be a protective response, sequestering potentially cytotoxic aggregates and also acting as a staging center for eventual autophagic clearance from the cell.

An aggresome forms around the microtubule organizing center in eukaryotic cells, adjacent to or enveloping the cell's centrosomes. Polyubiquitination tags the protein for retrograde transport via HDAC6 binding and microtubule-based motor protein, dynein. Moreover, substrates can also be targeted to the aggresome by a ubiquitin-independent pathway mediated by the stress-induced co-chaperone BAG3 (Bcl-2-associated athanogene 3), which transfers misfolded protein substrates bound to HSP70 (heat-shock protein 70) directly on to the microtubule motor dynein. The protein aggregate is then transported along the microtubule and unloaded via ATPase p97 forming the aggresome. Mediators such as p62 are believed to be involved in aggresome formation in sequestering omega-somes, which bind and increase the size of the aggresome. The aggresome is eventually targeted for autophagic clearance from the cell. Some pathological proteins, such as alpha-synuclein, cannot be degraded and cause the aggresomes to form inclusion bodies (in Parkinson's disease, Lewy bodies) which contribute to neuronal dysfunction and death.