PhD Transfer Examination – Dennison Trinh (Nash lab)

PhD Transfer Exam

Thursday May 4^th, 2:10 pm – Ramsay Wright Building, Rm. 432

Dennison Trinh (Nash lab)

“Validation of Sirtuin 3 as a Potential Disease-Modifying Agent in Parkinson’s Disease“

Abstract

With an aging population that becomes more susceptible to Parkinson’s Disease (PD), the lack of a treatment that can halt or reverse the progression of the disease results in hardships for the affected individual, their families, and their communities. Physical symptoms of PD include tremor, rigidity, and posterior instability, with aggregates of misfolded α-synuclein and ubiquitin forming as Lewy bodies in the substantia nigra pars compacta (SNc) region of the brain leading to dopaminergic neuron loss. While PD can be caused through familial and environmental factors, central to its pathology is the dysfunction of mitochondria. Dopaminergic neurons, which are high energy demanding cells, require proper mitochondrial health to regulate energy production and stress responses that rely on protein acetylation. Sirtuin 3 (SIRT3), a member of the Sirtuin family of NAD⁺ dependent proteins, is the main deacetylase in the mitochondria. Due to the link between protein deacetylation and mitochondrial health, the role of SIRT3 as a potential disease-modifying agent in the pre-formed fibril (PFF) model of PD in rats was examined. Through evaluations using the cylinder test to determine forelimb asymmetry and unbiased stereology to quantify the number of dopaminergic neurons in the SNc, the current data suggests that SIRT3 has a neuroprotective role in the Parkinsonian rat model. SIRT3 overexpressing rats showed a reduction in unimpaired forelimb bias and a protective effect on dopaminergic neurons (-2.737 ± 5.318 % asymmetry and 2093 ± 637.5 cells compared to -7.212 ± 9.539 % asymmetry and 1562 ± 278 cells in parkinsonian animals). The beneficial effects of SIRT3 were lost in rats overexpressing deacetylation deficient SIRT3, where forelimb bias and the number of dopaminergic neurons was comparable to parkinsonian animals (35.96 ± 8.871 % asymmetry and 1320 ± 379.4 cells). Currently, SIRT3’s neurorestorative capabilities are being studied, which would provide crucial support for SIRT3 being able to reverse the progression of PD. Based on these observations, the next steps are to investigate the mechanism in which SIRT3 acts as a therapeutic agent and to test the use of high-intensity focused ultrasound (HIFU) as a less invasive gene delivery tool for SIRT3 overexpression. These studies would therefore lay the foundation for SIRT3 to be developed into a potential therapeutic agent in PD patients in the future.

Ramsay Wright is a wheelchair accessible building.