Drosophila NMNAT Maintains Neural Integrity Independent of Its NAD Synthesis Activity

• DOI: 10.1371/journal.pbio.0040416
• Publication Date: 2006-11-22T21:44:54Z
• Authors: R. Grace Zhai; Yu Cao; P. Robin Hiesinger; Yi Zhou; Sunil Q Mehta; Karen L Schulze; Patrik Verstreken; Hugo J Bellen
• Keywords: Neurons; 0303 health sciences; QH301-705.5; NAD; Retina; Animals, Genetically Modified; Disease Models, Animal; Mice; 03 medical and health sciences; Nerve Degeneration; Animals; Drosophila; Mutant Proteins; Nicotinamide-Nucleotide Adenylyltransferase; Biology (General); Wallerian Degeneration; Research Article

Wallerian degeneration refers to a loss of the distal part an axon after nerve injury. slow (Wld(s)) mice overexpress chimeric protein containing NAD synthase NMNAT (nicotinamide mononucleotide adenylyltransferase 1) and exhibit delay in axonal degeneration. Currently, conflicting evidence raises questions as whether is protecting factor its enzymatic activity required for such possible function. Importantly, link between nmnat at present solely based on overexpression studies enzymatically active protein. Here we use visual system Drosophila model address these issues. We have isolated first mutations multicellular organism forward genetic screen synapse malfunction Drosophila. Loss causes rapid severe neurodegeneration that can be attenuated by blocking neuronal activity. Furthermore, vivo expression mutated shows inactive retains strong neuroprotective effects rescues phenotype caused nmnat. Our data indicate NAD-independent requirement maintaining integrity exploited protect neurons from activity-induced