The role of SIRT3 in homeostasis and cellular health.

Mitochondria are responsible for maintaining cellular energy levels, and play a major role in regulating homeostasis, which ensures physiological function from the molecular to whole animal. Sirtuin 3 (SIRT3) is the major protein deacetylase of mitochondria. SIRT3 serves as a nutrient sensor; under conditions of mild metabolic stress, SIRT3 activity is increased.

Parkinson's disease pathology is directly correlated to SIRT3 in human subjects and animal models: Implications for AAV.SIRT3-myc as a disease-modifying therapy.

In Parkinson's disease (PD), post-mortem studies in affected brain regions have demonstrated a decline in mitochondrial number and function. This combined with many studies in cell and animal models suggest that mitochondrial dysfunction is central to PD pathology. We and others have shown that the mitochondrial protein deacetylase, SIRT3, has neurorestorative effects in PD models.

Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3.

Background: Delivery of viral vectors as gene therapies to treat neurodegenerative diseases has been hampered by the inability to penetrate the blood brain barrier (BBB) and invasive or non-targeted delivery options prone to inducing immune responses. MR guided focused ultrasound (MR-g-FUS) and microbubbles have demonstrated safe, temporary, targeted BBB permeabilization clinically.

Methods: We developed clinically scalable, microbubble drug conjugates (MDCs) for the viral gene therapy, AAV.

The multi-faceted role of mitochondria in the pathology of Parkinson's disease.

Mitochondria are essential for neuronal function. They produce ATP to meet energy demands, regulate homeostasis of ion levels such as calcium and regulate reactive oxygen species that cause oxidative cellular stress. Mitochondria have also been shown to regulate protein synthesis within themselves, as well as within the nucleus, and also influence synaptic plasticity.

Dexras1 is a homeostatic regulator of exercise-dependent proliferation and cell survival in the hippocampal neurogenic niche.

Adult hippocampal neurogenesis is highly responsive to exercise, which promotes the proliferation of neural progenitor cells and the integration of newborn granule neurons in the dentate gyrus. Here we show that genetic ablation of the small GTPase, Dexras1, suppresses exercise-induced proliferation of neural progenitors, alters survival of mitotic and post-mitotic cells in a stage-specific manner, and increases the number of mature newborn granule neurons. Dexras1 is required for exercise-triggered recruitment of quiescent neural progenitors into the cell cycle.

Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonism.

Parkinson's disease (PD) is a neurodegenerative movement disorder, which affects approximately 1-2% of the population over 60years of age. Current treatments for PD are symptomatic, and the pathology of the disease continues to progresses over time until palliative care is required. Mitochondria are key players in the pathology of PD.