This grant builds upon the research from a prior grant: Validation of Sirtuin 3 as a Neuroprotective Target in Parkinson’s Disease
Objective/Rationale:
Dysfunctional mitochondria (powerhouses of the cell) are central to the pathology of Parkinson's Disease (PD). Sirtuins are a group of proteins that increase energetic processes within cells, resulting in protective effects that increase cellular longevity. Sirtuin 3 (SIRT3) is the most predominant Sirtuin within mitochondria. We have shown that increasing SIRT3 levels causes a reduction in cell death and corrects behavioral deficits in a pre-clinical model of PD. We will further validate SIRT3 as a neuroprotective agent in an additional model of PD.
Project Description:
To further validate the neuroprotective value of SIRT3, a pre-clinical model which exhibits pathological and behavioral abnormalities equivalent to those observed in those with PD, will be utilized. Genetically engineered viruses will be used to increase SIRT3 levels in the brain region that is most severely affected and closely linked with PD symptoms. SIRT3 levels will be elevated at two different stages of neuronal health: when neurons are healthy and when they are functionally impaired. The effect of increasing SIRT3 levels will be determined at different stages of PD pathology using behavioral and post-mortem studies.
Relevance to Diagnosis/Treatment of Parkinson's Disease:
In this study, we will simulate the pathological processes occurring in neurons at different stages of PD in a pre-clinical model and will test the neuroprotective potential of SIRT3 by infusing this protein into the brain region affected in PD (the substantia nigra). If SIRT3 restores impaired neurons back to a healthy state, it is likely to be an effective therapy in those with advanced PD. This study will also define the timepoint during the process of PD in which enhancing mitochondrial function by increasing SIRT3 levels will protect against the neurodegenerative processes associated with PD.
Anticipated Outcome:
The procedures outlined in this study will further validate whether SIRT3 is neuroprotective in an accepted pre-clinical model of PD. Furthermore, our work should reveal which groups of those with PD might benefit from SIRT3.