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      Ultrastructural Characterization of the Lower Motor System in a Mouse Model of Krabbe Disease

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          Abstract

          Krabbe disease (KD) is a neurodegenerative disorder caused by the lack of β- galactosylceramidase enzymatic activity and by widespread accumulation of the cytotoxic galactosyl-sphingosine in neuronal, myelinating and endothelial cells. Despite the wide use of Twitcher mice as experimental model for KD, the ultrastructure of this model is partial and mainly addressing peripheral nerves. More details are requested to elucidate the basis of the motor defects, which are the first to appear during KD onset. Here we use transmission electron microscopy (TEM) to focus on the alterations produced by KD in the lower motor system at postnatal day 15 (P15), a nearly asymptomatic stage, and in the juvenile P30 mouse. We find mild effects on motorneuron soma, severe ones on sciatic nerves and very severe effects on nerve terminals and neuromuscular junctions at P30, with peripheral damage being already detectable at P15. Finally, we find that the gastrocnemius muscle undergoes atrophy and structural changes that are independent of denervation at P15. Our data further characterize the ultrastructural analysis of the KD mouse model, and support recent theories of a dying-back mechanism for neuronal degeneration, which is independent of demyelination.

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          Simplified mammalian DNA isolation procedure.

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            Biology and pathology of nonmyelinating Schwann cells.

            The CNS contains relatively few unmyelinated nerve fibers, and thus benefits from the advantages that are conferred by myelination, including faster conduction velocities, lower energy consumption for impulse transmission, and greater stability of point-to-point connectivity. In the PNS many fibers or regions of fibers the Schwann do not form myelin. Examples include C fibers nociceptors, postganglionic sympathetic fibers, and the Schwann cells associated with motor nerve terminals at neuromuscular junctions. These examples retain a degree of plasticity and a capacity to sprout collaterally that is unusual in myelinated fibers. Nonmyelin-forming Schwann cells, including those associated with uninjured fibers, have the capacity to act as the "first responders" to injury or disease in their neighborhoods.
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              Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF.

              Neurodegenerative diseases can have long preclinical phases and insidious progression patterns, but the mechanisms of disease progression are poorly understood. Because quantitative accounts of neuronal circuitry affected by disease have been lacking, it has remained unclear whether disease progression reflects processes of stochastic loss or temporally defined selective vulnerabilities of distinct synapses or axons. Here we derive a quantitative topographic map of muscle innervation in the hindlimb. We show that in two mouse models of motoneuron disease (G93A SOD1 and G85R SOD1), axons of fast-fatiguable motoneurons are affected synchronously, long before symptoms appear. Fast-fatigue-resistant motoneuron axons are affected at symptom-onset, whereas axons of slow motoneurons are resistant. Axonal vulnerability leads to synaptic vesicle stalling and accumulation of BC12a1-a, an anti-apoptotic protein. It is alleviated by ciliary neurotrophic factor and triggers proteasome-dependent pruning of peripheral axon branches. Thus, motoneuron disease involves predictable, selective vulnerability patterns by physiological subtypes of axons, episodes of abrupt pruning in the target region and compensation by resistant axons.
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                Author and article information

                Contributors
                valentina.cappello@iit.it
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                5 December 2016
                5 December 2016
                2016
                : 6
                : 1
                Affiliations
                [1 ]Center for Nanotechnology Innovation@NEST, Istituto Italiano di Tecnologia Piazza San Silvestro, 12, 56127 Pisa, Italy
                [2 ]GRID grid.6093.c, , NEST, Scuola Normale Superiore, ; Piazza San Silvestro 12, 56127 Pisa, Italy
                [3 ]NEST, Istituto Nanoscienze-CNR, Piazza San Silvestro 12, 56127 Pisa, Italy
                [4 ]ISNI 0000 0000 9193 5936, GRID grid.478935.4, , Fondazione Umberto Veronesi, ; Piazza Velasca 5, 20122 Milano, Italy
                Author information
                http://orcid.org/0000-0002-7323-2174
                Article
                1
                10.1038/s41598-016-0001-8
                5431369
                28442746
                c55cae78-108b-43b6-badc-85c21194251d
                © The Author(s) 2016

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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                : 1 December 2015
                : 15 August 2016
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