title: Distinct pathways mediate axon degeneration during apoptosis and axon-specific pruning.
abstract: Neurons can activate pathways that destroy the whole cell via apoptosis or selectively degenerate only the axon (pruning). Both apoptosis and axon degeneration require Bax and caspases. Here we demonstrate that despite this overlap, the pathways mediating axon degeneration during apoptosis versus axon pruning are distinct. While Caspase-6 is activated in axons following nerve growth factor deprivation, microfluidic chamber experiments reveal that Caspase-6 deficiency only protects axons during axon-specific but not whole-cell (apoptotic) nerve growth factor deprivation. Strikingly, axon-selective degeneration requires the apoptotic proteins Caspase-9 and Caspase-3 but, in contrast to apoptosis, not apoptotic protease activating factor-1. Additionally, cell bodies of degenerating axons are protected from caspase activation by proteasome activity and X-linked inhibitor of apoptosis protein. Also, mature neurons restrict apoptosis but remain permissive for axon degeneration, further demonstrating the independent regulation of these two pathways. These results reveal insight into how neurons allow for precise control over apoptosis and axon-selective degeneration pathways, thereby permitting long-term plasticity without risking neurodegeneration.
authors.affiliation: Neurobiology Curriculum, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Corey L
authors.initials: CL
authors.lastname: Cusack
authors.forename: Vijay
authors.initials: V
authors.lastname: Swahari
authors.forename: W
authors.initials: W
authors.lastname: Hampton Henley
authors.forename: J
authors.initials: J
authors.lastname: Michael Ramsey
authors.forename: Mohanish
authors.initials: M
authors.lastname: Deshmukh
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009410:Nerve Degeneration / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D009414:Nerve Growth Factors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D053477:Apoptotic Protease-Activating Factor 1; D009414:Nerve Growth Factors; D051636:X-Linked Inhibitor of Apoptosis Protein; D045304:Cytochromes c; D020169:Caspases; D046988:Proteasome Endopeptidase Complex