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Extensive Remyelination of the CNS Leads to Functional Recovery

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Extensive Remyelination of the CNS Leads to Functional Recovery −3 x 10 11 A BC0.35 1 10 0.3 0.9 9 0.25 0.8 0.2 8 0.7 0.15 7 0.6 0.1 0.5 6 Correlation 0.4 0.05 Max. Frequency Max. Power Spectrum 5 0.3 0 4 0.2 −0.05 3 0.1 −0.1 2 0 −0.15 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Noise Level Noise Level Noise Level Fig. 5. Stochastic resonance effects. (A) Maximum of the power spectrum peak of the signal given by differences between the level of synchronization between both communities versus the noise level (variance). (B) Maximum in the power spectrum of the signal given by differences between the level of synchronization between both communities versus the noise level. (C) Correlation between the level of synchronization between both communities versus the noise level. Note the stochastic resonance effect that for the same level of fluctuations reveals the optimal emergence of 0.1-Hz global slow oscillations and the emergence of anticorrelated spatiotemporal patterns for both communities. Points (diamonds) correspond to numerical simulations, whereas the line corresponds to a nonlinear least-squared fitting using an ␣-function. www.pnas.org/cgi/doi/10.1073/pnas.0906701106 NEUROSCIENCE GENETICS Correction for ‘‘Extensive remyelination of the CNS leads to Correction for ‘‘Altered tumor formation and evolutionary functional recovery,’’ by I. D. Duncan, A. Brower, Y. Kondo, selection of genetic variants in the human MDM4 oncogene,’’ by J. F. Curlee, Jr., and R. D. Schultz, which appeared in issue 16, Gurinder Singh Atwal, Tomas Kirchhoff, Elisabeth E. Bond, April 21, 2009, of Proc Natl Acad Sci USA (106:6832–6836; first Marco Monagna, Chiara Menin, Roberta Bertorelle, Maria published April 2, 2009; 10.1073/pnas.0812500106). Chiara Scaini, Frank Bartel, Anja Bo¨hnke, Christina Pempe, The authors note that on page 6836, right column, first Elise Gradhand, Steffen Hauptmann, Kenneth Offit, Arnold J. paragraph, the fourth line appears incorrectly in part. The dose Levine, and Gareth L. Bond, which appeared in issue 25, June amount ‘‘25.0 and 50.0 Gy’’ should instead appear as ‘‘25–50 23, 2009, of Proc Natl Acad Sci USA (106:10236–10241; first kGy.’’ This error does not affect the conclusions of the article. published June 4, 2009; 10.1073/pnas.0901298106). The authors note that the author name Marco Monagna www.pnas.org/cgi/doi/10.1073/pnas.0906582106 should have appeared as Marco Montagna. The online version has been corrected. The corrected author line appears below. BIOPHYSICS AND COMPUTATIONAL BIOLOGY Gurinder Singh Atwal, Tomas Kirchhoff, Elisabeth E. Correction for ‘‘Dissection of the high rate constant for the Bond, Marco Montagna, Chiara Menin, Roberta binding of a ribotoxin to the ribosome,’’ by Sanbo Qin and Bertorelle, Maria Chiara Scaini, Frank Bartel, Anja Huan-Xiang Zhou, which appeared in issue 17, April 28, 2009, Bo¨ hnke, Christina Pempe, Elise Gradhand, Steffen of Proc Natl Acad Sci USA (106:6974–6979; first published April Hauptmann, Kenneth Offit, Arnold J. Levine, 3, 2009; 10.1073/pnas.0900291106). The authors note that Garcı´a-Mayoral et al. (42) also studied and Gareth L. Bond the interaction between loop 1 of the ribotoxin and ribosomal www.pnas.org/cgi/doi/10.1073/pnas.0907031106 protein L14 by docking their structures together. The present paper focuses on the binding kinetics. The reference citation appears below. 42. Garcı´a-MayoralF, et al. (2005) Modeling the highly specific ribotoxin recognition of ribosomes. FEBS Lett 579:6859–6864. www.pnas.org/cgi/doi/10.1073/pnas.0906817106 12208 ͉ www.pnas.org Downloaded by guest on October 2, 2021 Extensive remyelination of the CNS leads to functional recovery I. D. Duncana,1, A. Browerb, Y. Kondoa, J. F. Curlee, Jr.c, and R. D. Schultzd Departments of aMedical Sciences and dPathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI 53706; bWisconsin Veterinary Diagnostic Laboratory, 445 Easterday Lane, Madison, WI 53706; and cHarlan Laboratories, P.O. Box 44220, Madison, WI 53744 Edited by Hector F. DeLuca, University of Wisconsin, Madison, WI, and approved February 18, 2009 (received for review December 9, 2008) Remyelination of the CNS in multiple sclerosis is thought to be be a major therapeutic target in MS and the inherited human important to restore conduction and protect axons against degen- myelin disorders. eration. Yet the role that remyelination plays in clinical recovery of function remains unproven. Here, we show that cats fed an Results irradiated diet during gestation developed a severe neurologic Clinical Signs. Neurologic dysfunction began approximately 4 disease resulting from extensive myelin vacuolation and subse- months after the introduction of the irradiated diet and pre- quent demyelination. Despite the severe myelin degeneration, sented as a slowly progressive disorder. Cats developed ataxia axons remained essentially intact. There was a prompt endoge- and paresis of the hindlimbs. These signs worsened and 2 cats nous response by cells of the oligodendrocyte lineage to the became paraplegic. In some cats, vision as tested by the menace demyelination, with remyelination occurring simultaneously. Cats reflex was reduced or lost. The neurologic examination, in that were returned to a normal diet recovered slowly so that by 3–4 summary, suggested that these abnormalities were primarily months they were neurologically normal. Histological examination because of spinal cord disease with optic nerve involvement. of the CNS at this point showed extensive remyelination that was Over a period of 2–4 months, cats that were returned to a especially notable in the optic nerve where almost the entire nerve nonirradiated diet gradually recovered ambulation and had a was remyelinated. Biochemical analysis of the diet and tissues from normal neurologic examination with normal vision. affected cats showed no dietary deficiencies or toxic accumula- tions. Thus, although the etiology of this remarkable disease Pathological Changes Seen During Neurologic Dysfunction. Over the remains unknown, it shows unequivocally that where axons are course of observation of this disease, affected tissues from 10 preserved remyelination is the default pathway in the CNS in cats during active disease were studied. Gross lesions were not nonimmune-mediated demyelinating disease. Most importantly, it identified in the brain, spinal cord, or other organs in any of the confirms the clinical relevance of remyelination and its ability to cats. The primary abnormality in the brain and especially the restore function. spinal cord was white mater vacuolation. The spinal cord was affected at all levels but most notably in the ventral and lateral demyelination ͉ irradiated diet ͉ oligodendrocytes ͉ MS columns where demyelinated axons of all sizes were seen scat- tered throughout the neuropil (Fig. 1). In the dorsal columns, in emyelination of the CNS is a major pathological finding in some cases only mild vacuolation was seen in the fasciculus Dmany acquired and inherited human neurologic disorders. cuneatus. However, in some cats, the dorsal columns showed Multiple sclerosis (MS), in particular, is characterized by acute changes similar to those in the rest of the spinal white matter and and chronic demyelination, which results in a slowing or block of demyelinated axons could be seen in large groups below the pia nerve conduction with subsequent neurologic dysfunction. Both (Fig. 1). Remarkably, despite the severe vacuolation, axons acute and chronic demyelination may lead to axon loss with the appeared intact within degenerating myelin sheaths; frequently, eventual clinical progression of the disease to a chronic stage macrophages associated with myelin debris were seen within the from which clinical recovery does not occur. The CNS can vacuoles (Fig. 1). The preservation of axons was confirmed in respond to demyelination by endogenous repair or remyelina- silver-stained sections (see Fig. S1). Although vacuolation and tion, with the restoration of nerve conduction to affected fibers demyelination were profound, axons with thin myelin sheaths (1). Remyelination will also lead to the protection of demyeli- indicative of remyelination were also common in areas of myelin nated nerve fibers against their loss in ongoing disease as has degeneration. Remyelination was particularly pronounced in the been shown in both MS (2) and an experimental model of dorsal column in some cats, where many small-diameter axons demyelination of the corpus callosum (3). However, it remains with thin myelin sheaths were noted in the presence of ongoing unproven whether remyelination alone can lead to complete myelin breakdown. In cats that experienced loss of vision, the functional recovery, especially if extensive areas of the CNS are optic nerves showed extensive myelin degeneration with few involved. It has been suggested that other mechanisms such as intact myelinated fibers remaining (Fig. 2). These changes were nerve fiber plasticity through the redistribution of sodium chan- more severe than in the spinal cord, with demyelinated axons nels Nav 1.6 and 1.2 can restore conduction to demyelinated throughout the entire optic nerve associated with myelin-laden axons and may also be important in functional recovery (4). macrophages (Fig. 2). In the brain, a varying degree of white mater vacuolation was To date, there are no models of neurologic dysfunction caused noted in the corona radiata and crus cerebri in all 10 of the cats by widespread CNS demyelination that unequivocally define examined. This finding was also noted although less severe in the remyelination as the mechanism of functional recovery. Here, we describe a model in the cat in which severe neurologic dysfunction, including ataxia, paresis, paralysis, and vision loss, Author contributions: I.D.D., A.B., J.C., and R.D.S.
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