Degradation of Alpha-Synuclein

The ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway are two of the most important mechanisms to repair or remove abnormal proteins. An alteration in the function of either or both of these systems is thought to play a pivotal role in the pathogenesis of many neurodegenerative disorders, such as Parkinson's disease. The UPS is the major regulated protein degradation mechanism in the cell and is responsible for the highly selective degradation of short-lived intracellular and plasma membrane proteins under basal metabolic conditions, as well as misfolded or damaged proteins in the cytosol, nucleus or endoplasmic reticulum.

The system involves the targeting of susceptible proteins by ubiquitin and subsequent degradation within the proteasome barrel. The UPS-regulated proteolysis is emerging as part of neurodevelopment, synaptic function, and plasticity and survival of neurons. Recently, the redistribution of proteasomes from dendritic shafts to synaptic spines upon synaptic stimulation was reported, providing a mechanism for local protein degradation. Dysfunction of the UPS, leading to the accumulation of misfolded proteins, has been strongly implicated in the pathogenesis of Parkinson's disease. This hypothesis is supported by molecular genetic studies of Parkinson's disease-causing genes, including alpha-synuclein, parkin and UCHL1.

Several studies have investigated a link between alpha-synuclein and the proteasome, and findings show that mutant alpha-synuclein can reduce the net proteasomal activity in living cells. Importantly, recent studies suggest that soluble oligomeric intermediates of alpha-synuclein may specifically impair the function of the 26S proteasome; however, the mechanisms and the particular species involved remain elusive. Current research projects strive to elucidate the mechanisms of proteasomal-mediated degradation of misfolded alpha-synuclein to determine if excess toxic intermediate species of alpha-synuclein can lead to proteasome dysfunction.

As Mayo Clinic researchers discover ways in which the neurons clear the toxic forms of alpha-synuclein protein, target pathways can then be determined for therapeutic interventions.