NAD+ depletion causes neuronal death in rodent models of brain ischemia/reperfusion injury, Wallerian degeneration, multiple sclerosis and occurs after excitotoxic insults and oxidative stress. We have recently discovered that NAD+ depletion is also the primary cause of neuronal death induced by a misfolded and toxic form of the amyloidogenic prion protein (TPrP). These results established the role of NAD+ depletion in the pathogenesis of at least one protein misfolding neurodegenerative disease, a family of diseases that comprise, among others, Alzheimer's disease and Parkinson's disease. NAD+ replenishment reversed the fate of TPrP- injured neurons in culture and improved motor function in a mouse model of prion disease. In a pilot high- throughput screen we identified a compound restoring neuronal viability by NAD+ replenishment in TPrP- exposed cells. We hypothesize that its molecular target is a key effector in the TPrP-induced pathway and that deciphering the compound's mode of action will further our understanding of the mechanisms of NAD+ depletion prevalent in TPrP toxicity and possibly other debilitating brain conditions. In this focused research effort, we will use affinity-based methods combined with proteomics to identify the compound's molecular target relevant to its neuroprotective activity, determine its mode of action and probe its structure for enhanced activity. This knowledge will provide insights into degenerative pathways linked to NAD+ depletion and will support lead development efforts aiming at developing a neuroprotective drug.

Public Health Relevance

NAD+ is a metabolite essential for cell survival whose depletion is involved in neuronal death in a number of conditions including brain ischemia, nerve degeneration after axotomy, multiple sclerosis and, as we have recently discovered, misfolded prion protein (TPrP) toxicity. We have identified a chemical compound that replenishes NAD+ and rescues cells exposed to TPrP. We will identify the compound's intracellular target to understand its mode of action and support future lead development efforts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS093488-01A1
Application #
9111628
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Wong, May
Project Start
2016-04-01
Project End
2018-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458