Objective/Rationale:
Mitochondria are the major energy generators of a cell. Dysfunctional mitochondria are central to the pathology of Parkinson’s Disease (PD). We hypothesize that improving the health of mitochondria in the neurons of patients with PD will halt the progression of the disease.
The Sirtuins are a group of proteins that enhance energetic processes within cells resulting in protective effects to increase cellular longevity. Sirtuin 3 (SIRT3) is the most predominant Sirtuin within mitochondria. We hypothesize that elevating cellular SIRT3 levels will enhance mitochondrial health, causing a reduction in cell death, thus inhibiting the progression of PD.
Project Description:
To measure the neuroprotective value of SIRT3, one of the few pre-clinical models shown to exhibit pathological and behavioral abnormalities equivalent to those observed in PD patients – the a-synuclein pre-clinical model – will be utilized. Genetically engineered viruses will be used to elevate 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: (i) when neurons are healthy and (ii) when they are functionally impaired. The effect of elevating levels of SIRT3 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 the brains of a-synuclein pre-clinical models and test the neuroprotective potential of SIRT3 by infusing this protein into the brain region affected in PD (known as substantia nigra). If SIRT3 restores impaired neurons back to a healthy state, it is more likely to be an effective therapy in patients with advanced PD. This study will also define when during the pathological process of PD, that enhancing mitochondrial function, through the elevation of SIRT3 levels will protect against the neurodegenerative processes associated with PD.
Anticipated Outcome:
The procedures outlined in this study will determine whether SIRT3 is neuroprotective in an accepted pre-clinical model of PD. Furthermore, our work should reveal which groups of PD patients might benefit from enhanced levels of SIRT3.
Final Outcome
Mitochondria are the energy generators of all cells. Dysfunction of mitochondria is believed to be central to the pathology of Parkinson’s disease (PD). In this project, our goal was to enhance mitochondrial health in brain regions affected in PD, to prevent cells from dying using a pre-clinical model of PD. We aimed to improve mitochondrial health by increasing the amounts of a mitochondrial protein called Sirtuin 3 (SIRT3) using genetic manipulation. We found that increasing the amounts of SIRT3 prevented parkinsonian symptoms and cell death in our pre-clinical model of PD. These protective effects were observed when SIRT3 was given prior to initiating PD pathology. Also, excitingly, SIRT3 revered parkinsonian symptoms and prevented cell death when it was given at a time when cells were already showing signs of stress, and animals were exhibiting parkinsonism symptoms. These studies validate SIRT3 as a potential disease – modifying agent in Parkinson’s disease. Additional studies need to be carried out to further validate SIRT3’s potential.
Posters and Presentations
1. Gleave J.A., Lizal K.E., Thiele S.L, Nash J.E.* Is SIRT3 Neuroprotective in Parkinson’s Disease? Neuropharmacology Satellite Symposium (2013)
2. Gleave J.A.*, Nash J.E. Understanding the beneficial effects of SIRT3 in a rodent and cell models of Parkinson’s disease. International Association of Neurons and Brain Disease (2014).