title: The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.
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.
authors.affiliation: Department of Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Xiong
authors.forename: Yan
authors.initials: Y
authors.lastname: Hao
authors.forename: Kan
authors.initials: K
authors.lastname: Sun
authors.forename: Jiaxing
authors.initials: J
authors.lastname: Li
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Bibhudatta
authors.initials: B
authors.lastname: Mishra
authors.forename: Pushpanjali
authors.initials: P
authors.lastname: Soppina
authors.forename: Chunlai
authors.initials: C
authors.lastname: Wu
authors.forename: Richard I
authors.initials: RI
authors.lastname: Hume
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Collins
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology* / Q000473:pathology*; D015536:Down-Regulation / Q000235:genetics; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000378:metabolism*; D010641:Phenotype; D013569:Synapses / Q000201:enzymology / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D014855:Wallerian Degeneration / Q000201:enzymology / Q000473:pathology*
chemical_list: D029721:Drosophila Proteins; D020930:MAP Kinase Kinase Kinases; D009419:Nerve Tissue Proteins; D009612:Nicotinamide-Nucleotide Adenylyltransferase; D044767:Ubiquitin-Protein Ligases; C409633:HIW protein, Drosophila; C512899:wnd protein, Drosophila; C510972:Nmnat1 protein, mouse