title: Regulation of axon degeneration after injury and in development by the endogenous calpain inhibitor calpastatin.
abstract: Axon degeneration is widespread both in neurodegenerative disease and in normal neural development, but the molecular pathways regulating these degenerative processes and the extent to which they are distinct or overlapping remain incompletely understood. We report that calpastatin, an inhibitor of calcium-activated proteases of the calpain family, functions as a key endogenous regulator of axon degeneration. Calpastatin depletion was observed in degenerating axons after physical injury, and maintaining calpastatin inhibited degeneration of transected axons in vitro and in the optic nerve in vivo. Calpastatin depletion also occurred in a caspase-dependent manner in trophic factor-deprived sensory axons and was required for this in vitro model of developmental degeneration. In vivo, calpastatin regulated the normal pruning of retinal ganglion cell axons in their target field. These findings identify calpastatin as a key checkpoint for axonal survival after injury and during development, and demonstrate downstream convergence of these distinct pathways of axon degeneration.
authors.affiliation: Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA; Research and Early Development, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Robby M
authors.initials: RM
authors.lastname: Weimer
authors.forename: Dara
authors.initials: D
authors.lastname: Kallop
authors.forename: Olav
authors.initials: O
authors.lastname: Olsen
authors.forename: Zhuhao
authors.initials: Z
authors.lastname: Wu
authors.forename: Nicolas
authors.initials: N
authors.lastname: Renier
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Uryu
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051186:Armadillo Domain Proteins / Q000235:genetics / Q000378:metabolism; D019771:Axotomy; D001921:Brain / Q000166:cytology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000150:complications / Q000378:metabolism*; D013997:Time Factors; D014161:Transduction, Genetic; D014855:Wallerian Degeneration / Q000473:pathology / Q000503:physiopathology*
chemical_list: D051186:Armadillo Domain Proteins; D002135:Calcium-Binding Proteins; D002154:Calpain; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D020932:Nerve Growth Factor; D009419:Nerve Tissue Proteins; D009612:Nicotinamide-Nucleotide Adenylyltransferase; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C543961:SARM1 protein, mouse; C033668:calpastatin; C510972:Nmnat1 protein, mouse