title: A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis.
abstract: In multiple sclerosis, a common inflammatory disease of the central nervous system, immune-mediated axon damage is responsible for permanent neurological deficits. How axon damage is initiated is not known. Here we use in vivo imaging to identify a previously undescribed variant of axon damage in a mouse model of multiple sclerosis. This process, termed 'focal axonal degeneration' (FAD), is characterized by sequential stages, beginning with focal swellings and progressing to axon fragmentation. Notably, most swollen axons persist unchanged for several days, and some recover spontaneously. Early stages of FAD can be observed in axons with intact myelin sheaths. Thus, contrary to the classical view, demyelination-a hallmark of multiple sclerosis-is not a prerequisite for axon damage. Instead, focal intra-axonal mitochondrial pathology is the earliest ultrastructural sign of damage, and it precedes changes in axon morphology. Molecular imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD. Indeed, neutralization of ROS and RNS rescues axons that have already entered the degenerative process. Finally, axonal changes consistent with FAD can be detected in acute human multiple sclerosis lesions. In summary, our data suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy.
authors: Research Unit Therapy Development, Institute of Clinical Neuroimmunology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors: Ivana
authors: I
authors: Nikić
authors: Doron
authors: D
authors: Merkler
authors: Catherine
authors: C
authors: Sorbara
authors: Mary
authors: M
authors: Brinkoetter
authors: Mario
authors: M
authors: Kreutzfeldt
authors: Florence M
authors: FM
authors: Bareyre
authors: Wolfgang
authors: W
authors: Brück
authors: Derron
authors: D
authors: Bishop
authors: Thomas
authors: T
authors: Misgeld
authors: Martin
authors: M
authors: Kerschensteiner
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D008262:Macrophage Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000473:pathology; D046529:Microscopy, Electron, Transmission; D018715:Microscopy, Video; D009103:Multiple Sclerosis / Q000473:pathology*; D009186:Myelin Sheath / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology; D018384:Oxidative Stress; D026361:Reactive Nitrogen Species / Q000037:antagonists & inhibitors / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000633:toxicity
chemical_list: D016166:Free Radical Scavengers; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species