Neurochemistry Pharmacology Laboratory
Research
In the Neurochemistry Pharmacology laboratory our research aims are 1) to understand the relationship between NAD+ metabolism and neurodegenerative disease and 2) identify suitable pharmacological drug targets in the NAD+ synthetic/metabolic pathways.
NAD+
NAD+ is the parent compound of the pyridine nucleotide family of coenzymes (NADH, NADP, NADPH) that act as essential cofactors and electron transporters in a number of metabolic processes including alcohol, lactate and amino acid metabolism and energy (ATP) production. It has also been recently observed that NAD+ is an essential substrate for several important NAD-dependent enzymes including:
NAD glycohydrolase (CD38+), affecting intracellular calcium signalling.
Poly(ADP-ribose) polymerase (PARP), affecting DNA repair.
Silent Information Regulator 2 (Sir2), an NAD-dependent deacetylase, affecting gene silencing and cellular longevity.
NAD+ has also been shown to activate the cellular energy-sensing enzyme AMP-activated protein kinase (AMPK).
The involvement of NAD+ in these key processes suggests that NAD+ is a key player in cellular control mechanisms. Maintenance of NAD+ is therefore essential for normal cell function. Our lab and others have consistently shown that critical loss of intracellular NAD+, particularly following oxidative stress, results in cell death in a number of cell types in the brain.
Increased NAD+ turnover
The most significant contributor to rapid NAD+ turnover and depletion is activation of the nuclear DNA repair enzyme poly(ADP-ribose)polymerase (PARP-1). PARP is activated when reactive oxygen species (ROS) induce double or single stranded breaks to the DNA. PARP uses up NAD+ to produce ADP-ribose polymers; an essential step in the base excision repair process. However, critical depletion of NAD+ by this process results in ATP depletion and a cascade of events leading to cell death.
Increased production of ROS occurs in a number of conditions including excess exposure to U.V. light or ionising radiation (x-ray, γ rays), chemical agents, infection, inflammation or reduced mitochondrial efficiency.
NAD+ and neurodegenerative disease
Alzheimer’s and Parkinson’s diseases are examples of neurodegenerative disorders characterised by progressive loss of neuronal cells. The primary cause of brain cell death is not known but appears to be mediated by inflammatory changes involving ROS and accelerated DNA damage. Improving antioxidant capacity and DNA repair are therefore mechanism through which cell viability may be promoted and retained.
As NAD+ plays a central role in DNA repair and intracellular levels are rapidly reduced during oxidative stress, strategies aimed at preserving or promoting NAD+ metabolism are therefore a promising therapeutic target for neurodegenerative disease.
Current Research
Using a combination of in vivo (human studies) and in vitro (human neuronal and brain cell culture) models my lab is exploring the role of NAD+ metabolism in health and disease.
Specifically my lab is investigating the role of NAD+ in the following areas:
- Testing potential inhibition and modulation effects of selected NAD+ metabolic enzymes by natural and synthetic compounds on NAD+ metabolism and cell viability on brain cells.
- Quantitative tracer analyses of NAD+ synthesis from tryptophan using human brain cells in culture and mass spectrometry (LC-MS/MS).
- Assessing the efficacy of increased NAD+ anabolism on cell viability in models of neurodegenerative disease.
- Characterising the in-vivo effects of selected, NAD+ synthesis targeted molecules on nuclear enzyme activity and metabolism of selected cofactors.