Biochemical and Cellular Characterization of NMN Adenylyltransferase 2: A Brain Specific Isoform of an Essential NAD Synthesizing Enzyme
Mayer, Paul Robards, III
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NMN adenylyltransferase 2 (Nmnat2) is one of three vertebrate enzymes that catalyze the synthesis of NAD from NMN and ATP. Nmnat1, -2 and -3 are each expressed from a separate gene and are distinguished from one another by their expression, subcellular localization and enzyme kinetics. Nmnat overexpression in neurons slows the rate of axon degeneration. This phenotype requires Nmnat activity and is caspase-independent suggesting that neuronal NAD metabolism regulates a novel program of self-destruction in axons. Nmnat2 is detected exclusively in the brain, unlike Nmnat1 and Nmnat3, which are widely expressed. Furthermore, Nmnat2 localizes to the Golgi complex in HeLa cells. Taken together, these observations suggest that Nmnat2 may have a specialized role in NAD metabolism in the brain. The goal of the work presented here is essentially to describe the molecular interactions of Nmnat2 and to attempt to understand what role Nmnat2 fulfills in the brain that cannot be met by Nmnat1 or Nmnat3. As described here, I have discovered that Nmnat2 is a neuronal peripheral membrane protein anchored via palmitoylation that localizes to dendrites and the cell body. Furthermore, I argue that a low level of Nmnat2 in the axon, or possibly its exclusion altogether, is required for normal (i.e. fast) axon degeneration, providing a rationale for its membrane association and rapid turnover.