Proper brain function requires an active maintenance program to sustain neuronal health. In essence, neurons and glia have to repair the damage that is induced by neuronal activity, injury, toxins, and aging. Environmental stressors impact the nervous system and lead to neuronal dysfunction and degeneration if the protective mechanisms are weakened. Recent studies revealed that NMNATs (nicotinamide mononucleotide adenylyl transferase) maintain neuronal integrity and facilitate proper neural function throughout life. NMNAT2 is the major NMNAT isoform expressed in the mammalian brain and is extremely labile with a short half-life in neurons. We and others have found that NMNAT2 levels are significantly reduced in CNS tissues from patients with Alzheimer's disease, tauopathies, or Parkinson's disease. Reducing NMNAT2 function in mice leads to axonal deterioration, while NMNAT2 overexpression offers neuroprotection. In the proposed work we will address three specific aims: How does NMNAT2 reduce toxic tau species and protect neurons against tauopathy? Is NMNAT2 required to maintain neuronal health in adult brains? Is small molecule up-regulation of NMNAT2 levels neuroprotective? A combination of molecular/biochemical, genetic, anatomical, electrophysiological, imaging, viral vector and high-throughput screening approaches will be employed to accomplish these aims. This study will provide insight into how NMNAT2 maintains neuronal health in mature brains. NMNATs are potential drug targets for therapeutic interventions in neurodegeneration. A detailed knowledge on how NMNAT2 maintain neuronal integrity and its role in neuroprotection is critical not only for understanding normal brain function, but will also provide necessary insights to assist in drug discovery.

Public Health Relevance

More than six million Americans suffer from neurodegenerative diseases. We are studying how a protein called NMNAT2 provides neuroprotection in the mammalian central nervous system with a long-term goal of developing therapies to treat neurodegenerative diseases, including Alzheimer's disease and tauopathies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01NS086794-01A1
Application #
8813962
Study Section
Cell Death and Injury in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030