MSc Exit Seminar – Lindsay Arathoon – Monday, September 11th, 2017

MSc Exit Seminar

Monday, September 11, 2017 at 10:10 am, Ramsay Wright Building, Room 432

Lindsay Arathoon (Nash Lab)

Validation of Sirtuin 3 as a Neuroprotective and Neurorestorative Target in the mutant human A53T V-synuclein rat model of Parkinson’s Disease

Abstract:

Dysfunction of the mitochondrial plays a major role in the progressive and pathological development of Parkinson’s disease (PD). The exact mechanisms by which these detrimental circumstances arise have been highly researched, but are still yet to be elucidated. Evidence suggests that boosting mitochondrial function would have disease-modifying benefits to PD patients. In non-neuronal cells, mitochondrial protein deacetylase sirtuin 3 (SIRT3) is linked with cytoprotection and maintains mitochondrial acetylation levels to regulate cellular respiration enzymes, reduce mitochondrial bioenergetic demands, and improve mitochondrial response to oxidative stress by assisting in the reduction of reactive oxygen species (ROS). It was hypothesized that overexpression of SIRT3 in the substantia nigra pars compacta (SNc) would have neuroprotective and neurorestorative disease-modifying effects in a well-accepted, recombinant adeno-associated virus (rAAV) human mutant alpha-synuclein (A53T) rat model of PD. To examine this, rAAV expressing recombinant SIRT3-myc was infused into the SNc either seven days before or 18 days after rAAV A53T infusion. For the neuroprotection study, three weeks following A53T administration, parkinsonian animals showed a significant increase in forelimb asymmetry and striatal dopamine metabolism compared to the control animals, but no change in SNc cell count. At six weeks following administration of A53T, SIRT3 overexpression significantly prevented motor impairment, reversed changes in striatal dopamine turnover, and reduced cell death in comparison to untreated parkinsonian rats. For the neurorestoration study, where SIRT3 was infused after A53T when parkinsonian deficits are apparent, 3 weeks post-A53T injection there was a significant increase in forelimb asymmetry in parkinsonian rats compared to controls, but no change in TH-positive cell count in the SN or striatal dopamine turnover. However at six weeks following A53T administration, SIRT3 significantly decreased motor deficits and prevented degeneration of SN dopaminergic neurons compared to untreated parkinsonian rats. In isolated SN mitochondria of 6-week parkinsonian and SIRT3-treated rats, SIRT3 was observed to target the mitochondria and function as a protein deacetylase. These studies suggest that SIRT3 overexpression has a beneficial impact in the rAAV A53T model of PD, which may fundamentally designate it as a possible disease-modifying therapeutic agent for patients with PD.