Institution: Auburn University
The ubiquitin-proteasome system (UPS) is the pathway for degradation of nuclear and cytosolic proteins that are aged, damaged, or misfolded. Malfunctions in the UPS have been implicated in a wide variety of neurodegenerative diseases. Some proteins, when not properly degraded through the UPS, tend to form aggregates by binding to one another to form an insoluble structure that is very difficult to disassemble. Some have hypothesized that protein aggregation is toxic to cells, while others argue that the potentially toxic species are the proteins themselves, and that aggregation protects cells from improperly degraded proteins.Sequestosome 1/p62 is a protein that contains multiple binding domains, and serves a variety of cellular functions. Recent evidence suggests that p62 shuttles some proteins for degradation through the UPS. p62 has been found in protein aggregates from many UPS dysfunction-related diseases, such as Alzheimers disease, Parkinsons disease, and Huntingtons disease. Many of the components of neurodegenerative disease aggregates have been studied for their ability to form independent aggregates in vitro and in vivo. In this review, the UPS and protein aggregation are described and the role of p62 in each pathway is discussed, along with their relation to neurodegenerative disease.