Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death.

Abstract

Hypoxic-ischemic (H-I) injury to the developing brain is a significant cause of morbidity and mortality in humans. Other than hypothermia, there is no effective treatment to prevent or lessen the consequences of neonatal H-I. Increased expression of the NAD synthesizing enzyme nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) has been shown to be neuroprotective against axonal injury in the peripheral nervous system. To investigate the neuroprotective role of Nmnat1 against acute neurodegeneration in the developing CNS, we exposed wild-type mice and mice overexpressing Nmnat1 in the cytoplasm (cytNmnat1-Tg mice) to a well-characterized model of neonatal H-I brain injury. As early as 6 h after H-I, cytNmnat1-Tg mice had strikingly less injury detected by MRI. CytNmnat1-Tg mice had markedly less injury in hippocampus, cortex, and striatum than wild-type mice as assessed by loss of tissue volume 7 d days after H-I. The dramatic protection mediated by cytNmnat1 is not mediated through modulating caspase3-dependent cell death in cytNmnat1-Tg brains. CytNmnat1 protected neuronal cell bodies and processes against NMDA-induced excitotoxicity, whereas caspase inhibition or B-cell lymphoma-extra large (Bcl-XL) protein overexpression had no protective effects in cultured cortical neurons. These results suggest that cytNmnat1 protects against neonatal HI-induced CNS injury by inhibiting excitotoxicity-induced, caspase-independent injury to neuronal processes and cell bodies. As such, the Nmnat1 protective pathway could be a useful therapeutic target for acute and chronic neurodegenerative insults mediated by excitotoxicity.

• Authors: Philip B Verghese, Yo Sasaki, Donghan Yang, Floy Stewart, Fatima Sabar, Mary Beth Finn, Christine M Wroge, Steven Mennerick, Jeffrey J Neil, Jeffrey Milbrandt, David M Holtzman
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 47 Pg. 19054-9 (Nov 22 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 22058226 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• L-Lactate Dehydrogenase
• NMNAT1 protein, human
• Nicotinamide-Nucleotide Adenylyltransferase

Topics

• Analysis of Variance
• Animals
• Animals, Newborn
• Cell Death (physiology)
• Chromatography, High Pressure Liquid
• Humans
• Hypoxia-Ischemia, Brain (complications, pathology)
• Immunohistochemistry
• L-Lactate Dehydrogenase (metabolism)
• Magnetic Resonance Imaging
• Mice
• Necrosis (metabolism)
• Nerve Degeneration (enzymology, etiology, pathology)
• Nicotinamide-Nucleotide Adenylyltransferase (metabolism)