ArticlePLoS biology2012
The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.
Article in PLoS biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 140 papers.
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Who cites it
140 citing papers in PubMed, 203 citations in OpenAlex.
- Significance of NAD anabolism profiles in neurological diseases.Metabolic brain disease · 2026Review
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- ACL injury reprograms quadriceps myonuclear epigenetic and transcriptional signatures in mice.Molecular medicine (Cambridge, Mass.) · 2026Article
- Conserved Pathways, Divergent Outcomes: A Cross-Species Genomic Perspective on the Cancer-Neurodegeneration Paradox.International journal of molecular sciences · 2026Review
- Neuronal guidance signaling in neurodegenerative diseases: Key regulators that function at neuron-glia and neuroimmune interfaces.Neural regeneration research · 2026Article
- Programmed axon degeneration: mechanism, inhibition and therapeutic potential.Nature reviews. Neuroscience · 2026Review
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- Ubiquitin ligase signalling networks shape presynaptic development, function and disease.The Journal of physiology · 2025Review
- The Roles of Moonlighting Nicotinamide Mononucleotide Adenylyl Transferases in Cell Physiology.International journal of molecular sciences · 2025Review
- Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection.Molecular metabolism · 2025Article
- Peripheral Nerve Crush inCold Spring Harbor protocols · 2025Article
- Stepwise activation of SARM1 for cell death and axon degeneration revealed by a biosynthetic NMN mimic.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
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- Molecular regulation of axon termination in mechanosensory neurons.Development (Cambridge, England) · 2024Review
- SARM1-Dependent Axon Degeneration: Nucleotide Signaling, Neurodegenerative Disorders, Toxicity, and Therapeutic Opportunities.The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2024Review
- Article
- NADAntioxidants & redox signaling · 2023Review
- Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor function.bioRxiv : the preprint server for biology · 2023Article
- Deubiquitination of SARM1 by USP13 regulates SARM1 activation and axon degeneration.Life medicine · 2023Article
80 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Axonal degeneration is a hallmark of many neuropathies, neurodegenerative diseases, and injuries. Here, using a Drosophila injury model, we have identified a highly conserved E3 ubiquitin ligase, Highwire (Hiw), as an important regulator of axonal and synaptic degeneration. Mutations in hiw strongly inhibit Wallerian degeneration in multiple neuron types and developmental stages. This new phenotype is mediated by a new downstream target of Hiw: the NAD+ biosynthetic enzyme nicotinamide mononucleotide adenyltransferase (Nmnat), which acts in parallel to a previously known target of Hiw, the Wallenda dileucine zipper kinase (Wnd/DLK) MAPKKK. Hiw promotes a rapid disappearance of Nmnat protein in the distal stump after injury. An increased level of Nmnat protein in hiw mutants is both required and sufficient to inhibit degeneration. Ectopically expressed mouse Nmnat2 is also subject to regulation by Hiw in distal axons and synapses. These findings implicate an important role for endogenous Nmnat and its regulation, via a conserved mechanism, in the initiation of axonal degeneration. Through independent regulation of Wnd/DLK, whose function is required for proximal axons to regenerate, Hiw plays a central role in coordinating both regenerative and degenerative responses to axonal injury.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.