title: The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction.
abstract: Axon degeneration is an evolutionarily conserved process that drives the loss of damaged axons and is an early event in many neurological disorders, so it is important to identify the molecular constituents of this poorly understood mechanism. Here, we demonstrate that the Phr1 E3 ubiquitin ligase is a central component of this axon degeneration program. Loss of Phr1 results in prolonged survival of severed axons in both the peripheral and central nervous systems, as well as preservation of motor and sensory nerve terminals. Phr1 depletion increases the axonal level of the axon survival molecule nicotinamide mononucleotide adenyltransferase 2 (NMNAT2), and NMNAT2 is necessary for Phr1-dependent axon stability. The profound long-term protection of peripheral and central mammalian axons following Phr1 deletion suggests that pharmacological inhibition of Phr1 function may be an attractive therapeutic candidate for amelioration of axon loss in neurological disease.
authors.affiliation: Department of Developmental Biology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Babetto
authors.forename: Bogdan
authors.initials: B
authors.lastname: Beirowski
authors.forename: Emilie V
authors.initials: EV
authors.lastname: Russler
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
authors.forename: Aaron
authors.initials: A
authors.lastname: DiAntonio
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D014750:Vincristine / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D034741:RNA, Small Interfering; D014750:Vincristine; C532954:Mycbp2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C579543:Nmnat2 protein, mouse