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Cited by 166Nerve injury and regenerationNeurobiology and Insect Physiology ResearchHereditary Neurological Disorders

Drosophila NMNAT Maintains Neural Integrity Independent of Its NAD Synthesis Activity

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Zhai, R. Grace, Cao, Yu, Hiesinger, P. Robin, Zhou, Yi, Mehta, Sunil Q, Schulze, Karen L, Verstreken, Patrik, Bellen, Hugo J·2006·PLoS Biology
DOI 10.1371/journal.pbio.0040416PMC PMC1665629
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Abstract

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

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Authors
Zhai, R. G., Cao, Y., Hiesinger, P. R., Zhou, Y., Mehta, S. Q., Schulze, K. L., Verstreken, P., & Bellen, H. J.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Baylor College of Medicine (US)
Corresponding author
Bellen, Hugo J
ORCID
Venue
PLoS Biology
Publisher
Public Library of Science (PLoS)
Published
2006-11-28
Volume
4
Issue
12
Pages
e416
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.0040416
PMC
PMC1665629
OpenAlex
W2072989363
Cited by
166
References
2
Citations by year
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FWCI
2.91
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Lirias (KU Leuven) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Belgian American Educational Foundation
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
nicotinamide mononucleotide adenylyltransferase, axonal degeneration, Wallerian degeneration, neurodegeneration, neuronal activity, Drosophila visual system, neuronal integrity
MeSH terms
Animals, Disease Models, Animal, Drosophila, NAD, Nerve Degeneration, Neurons, Nicotinamide-Nucleotide Adenylyltransferase, Retina, Wallerian Degeneration, Animals, Genetically Modified, Mutant Proteins, Mice

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