title: An Atypical SCF-like Ubiquitin Ligase Complex Promotes Wallerian Degeneration through Regulation of Axonal Nmnat2.
abstract: Axon degeneration is a tightly regulated, self-destructive program that is a critical feature of many neurodegenerative diseases, but the molecular mechanisms regulating this program remain poorly understood. Here, we identify S-phase kinase-associated protein 1A (Skp1a), a core component of a Skp/Cullin/F-box (SCF)-type E3 ubiquitin ligase complex, as a critical regulator of axon degeneration after injury in mammalian neurons. Depletion of Skp1a prolongs survival of injured axons in vitro and in the optic nerve in vivo. We demonstrate that Skp1a regulates the protein level of the nicotinamide adenine dinucleotide (NAD)+synthesizing enzyme nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) in axons. Loss of axonal Nmnat2 contributes to a local ATP deficit that triggers axon degeneration. Knockdown of Skp1a elevates basal levels of axonal Nmnat2, thereby delaying axon degeneration through prolonged maintenance of axonal ATP. Consistent with Skp1a functioning through regulation of Nmnat2, Skp1a knockdown fails to protect axons from Nmnat2 knockdown. These results illuminate the molecular mechanism underlying Skp1a-dependent axonal destruction.
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yamagishi
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA. Electronic address: marctl@stanford.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology* / Q000473:pathology*; D002478:Cells, Cultured; D004734:Energy Metabolism; D051379:Mice; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000172:deficiency / Q000378:metabolism*; D009900:Optic Nerve / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014855:Wallerian Degeneration / Q000201:enzymology* / Q000473:pathology*
chemical_list: D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins; D044767:Ubiquitin-Protein Ligases; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C579543:Nmnat2 protein, mouse
keywords: E3 ubiquitin ligase; Wallerian degeneration; neurodegeneration; nicotinamide/nicotinic acid mononucleotide adenylyltransferase