Aggresome

An aggresome is a proteinaceous inclusion body that forms when cellular degradation machinery is impaired or overwhelmed, leading to an accumulation of protein for disposal. The aggresomal response is believed to be a generalised-protective cell biological response to the presence of a high load of abnormal or damaged protein within the cytosol of a cell which fails to be eliminated by the usual ubiquitin proteasome system for protein degradation.

Bio-genesis

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. Polyubiquitintation tags the protein for retrograde transport via HDAC6 binding and microtubule-based motor protein, dynein.^[1] Moreover, substrates can also be targeted to the aggreome by an 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.^[2] The protein aggregate is then transported along the microtubule and unloaded via 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 aggreseome. The aggreseome is eventually targeted for autophagic clearance for the cell. Some pathological proteins, such as a-synuclein, cannot be degraded and cause the aggresomes to form inclusion bodies, or in Parkinsons Lewy bodies, which contribute to neuronal dysfunction and death.^[3]

Human Disease

Certain cellular inclusions seen in human disease are thought to represent an aggresomal response, such as the Lewy body seen in neurons in the brain in Parkinson's disease and Mallory's Hyaline seen in liver cells in conditions such as alcoholic liver disease.

References

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