Objective/Rationale:
The cellular mechanisms that normally limit accumulation of alpha-synuclein are unclear. We have found that the enzyme, Nedd4, tags alpha-synuclein for destruction in lysosomes and thus helps protect against accumulation of this molecule in normal brain. These findings suggest that overproduction of this enzyme may combat the toxic buildup of alpha-synuclein characteristic of Parkinson’s and other neurodegenerative diseases.
Project Description:
These studies will involve using specially constructed viruses to increase alpha-synuclein content in parts of the brain that are affected in Parkinson’s disease. In addition, we shall in another pre-clinical model also overproduce the enzyme, Nedd4, and then compare their behavior and brain structure to see if Nedd4 reduces the accumulation of alpha-synuclein in the basal ganglia and if it protects against neural loss and behavioral abnormalities described previously. In addition, we shall carry out biochemical assays in vitro to test if certain variants of alpha-synuclein found in patients accumulate because their abnormal structures protects them from Nedd4-mediated destructions.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our recent experiments have indicated that the enzyme, Nedd4, is important in destruction of alpha-synucleins and thus appear likely to be a factor in slowing development of this disease. These studies are aimed at validating whether it would be justified to attempt to develop new pharmacological methods to treat or slow progression of Parkinson’s disease by stimulating the activity of Nedd4 in brain or increasing its content. It should also indicate if any disease-related species of alpha-synuclein may normally escape this protective effect of Nedd4.
Anticipated Outcome:
These studies should indicate whether activation of the ubiquitination enzyme, Nedd4, is able to reduce alpha-synuclein content in rat brain and its toxic consequences. If such effects are demonstrated, it would justify initiation of drug development programs to activate or to overproduce Nedd4.
Final Outcome
The accumulation of alpha-synuclein in neurons is a critical factor in the development of Parkinson’s disease, therefore we have been studying the cellular mechanism for breakdown of this protein. Our studies indicate a key role of the enzyme Nedd4 in modifying alpha-synuclein by linking it to a chain of ubiquitin molecules (small regulatory proteins that direct proteins to be recycled). This modification targets alpha-synuclein for degradation in lysosomes. Our recent studies have shown what parts of alpha-synuclein are recognized by Nedd4, that increasing or decreasing Nedd4 content in cells alters alpha-synuclein accumulation, and that in the brains of Parkinson’s disease patients, Nedd4 is present in increased amounts around affected neurons, apparently as a novel defense mechanism against this disease.