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The Ubiquitin/Proteasome System (UPS) is a highly regulated mechanism of intracellular protein degradation and turnover. Through the concerted actions of a series of enzymes, proteins are marked for proteasomal degradation by being linked to the polypeptide co-factor, ubiquitin. The UPS participates in a wide array of biological functions such as antigen presentation, regulation of gene transcription and the cell cycle, and activation of NF-κB.
Ubiquitin (Ub) is a polypeptide, 76 amino acids in length, which acts as a molecular label within the UPS. Each Ub polypeptide has seven lysine residues; these are involved in linking multiple Ub polypeptides together to form a polyubiquitin chain. The pattern and distribution of ubiquitination determines the final fate of a protein. For example, monoubiquitination has been linked to endocytosis, protein sorting, nuclear export of proteins, DNA repair and transcription regulation, whilst polyubiquitination signals protein degradation, DNA repair, kinase activation and transcription factor activation.
The process by which proteins are ubiquitinated comprises three main steps:
Protein targets of the UPS include regulators of cell cycle and apoptosis, transcription factors involved in the regulation of cell division, growth, differentiation, signal transduction and response to stress, and therefore the UPS is linked to a multitude of cellular processes. As an example, the UPS components MDM2 and Cullin 3, both E3 ligases, are key regulators of the DNA damage response and the Nrf2 pathway respectively, preventing the inappropriate activation of cellular stress responses.
Dysregulation of the UPS has been linked to a wide variety of diseases, including neurological disorders, cancer and atherosclerosis. Its function is of particular interest in protein-misfolding disorders such as Parkinson's disease and Huntington's disease, where aberrant UPS activity is thought to contribute to the intracellular accumulation of toxic proteins.
Though ubiquitination is one of the main mechanisms for initiating proteasomal degradation of a target protein, emerging evidence suggests that proteins may also be degraded via ubiquitin-independent mechanisms. An example of this is the ubiquitin-independent degradation of topoisomerase IIβ following its persistent interference with RNA polymerase II activity.
Parkinson's disease (PD) causes chronic disability and is the second most common neurodegenerative condition. This poster outlines the neurobiology of the disease, as well as highlighting current therapeutic treatments for symptomatic PD, and emerging therapeutic strategies to delay PD onset and progression.