title: Sensory neuropathy in progressive motor neuronopathy (pmn) mice is associated with defects in microtubule polymerization and axonal transport.
abstract: Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) are now recognized as multi-system disorders also involving various non-motor neuronal cell types. The precise extent and mechanistic basis of non-motor neuron damage in human ALS and ALS animal models remain however unclear. To address this, we here studied progressive motor neuronopathy (pmn) mice carrying a missense loss-of-function mutation in tubulin binding cofactor E (TBCE). These mice manifest a particularly aggressive form of motor axon dying back and display a microtubule loss, similar to that induced by human ALS-linked TUBA4A mutations. Using whole nerve confocal imaging of pmn × thy1.2-YFP16 fluorescent reporter mice and electron microscopy, we demonstrate axonal discontinuities, bead-like spheroids and ovoids in pmn suralis nerves indicating prominent sensory neuropathy. The axonal alterations qualitatively resemble those in phrenic motor nerves but do not culminate in the loss of myelinated fibers. We further show that the pmn mutation decreases the level of TBCE, impedes microtubule polymerization in dorsal root ganglion (DRG) neurons and causes progressive loss of microtubules in large and small caliber suralis axons. Live imaging of axonal transport using GFP-tagged tetanus toxin C-fragment (GFP-TTC) demonstrates defects in microtubule-based transport in pmn DRG neurons, providing a potential explanation for the axonal alterations in sensory nerves. This study unravels sensory neuropathy as a pathological feature of mouse pmn, and discusses the potential contribution of cytoskeletal defects to sensory neuropathy in human motor neuron disease.
authors.affiliation: Department of Anesthesiology and Research Center Translational Neurosciences, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schäfer
authors.affiliation: Institut de Neurosciences de la Timone, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université UMR 7289, Marseille, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bellouze
authors.affiliation: Institut de Neurosciences de la Timone, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université UMR 7289, Marseille, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquier
authors.affiliation: Institut de Neurosciences de la Timone, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université UMR 7289, Marseille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Schaller
authors.affiliation: Laboratoire de Neurologie, Centre de référence national "Neuropathies périphériques rares", Centre Hospitalo-Universitaire (CHU), Limoges, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Richard
authors.affiliation: Department of Neurology, Centre Hospitalo-Universitaire (CHU) Poitiers, University of Poitiers, Poitiers, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mathis
authors.affiliation: Laboratoire de Neurologie, Centre de référence national "Neuropathies périphériques rares", Centre Hospitalo-Universitaire (CHU), Limoges, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vallat
authors.affiliation: Institut de Neurosciences de la Timone, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université UMR 7289, Marseille, France.
authors.forename: Georg
authors.initials: G
authors.lastname: Haase
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D008870:Microtubules / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D018832:Molecular Chaperones / Q000235:genetics; D016472:Motor Neuron Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010523:Peripheral Nervous System Diseases / Q000209:etiology* / Q000473:pathology*; D010791:Phrenic Nerve / Q000473:pathology / Q000648:ultrastructure; D058105:Polymerization; D013497:Sural Nerve / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure
chemical_list: D018832:Molecular Chaperones; C469269:Tbce protein, mouse
keywords: axon degeneration; microtubule; motor neuron disease; sensory neuropathy; spheroid