title: Disrupted axon-glia interactions at the paranode in myelinated nerves cause axonal degeneration and neuronal cell death in the aged Caspr mutant mouse shambling.
abstract: Emerging evidence suggests that axonal degeneration is a disease mechanism in various neurodegenerative diseases and that the paranodes at the nodes of Ranvier may be the initial site of pathogenesis. We investigated the pathophysiology of the disease process in the central and peripheral nervous systems of a Caspr mutant mouse, shambling (shm), which is affected by disrupted paranodal structures and impaired nerve conduction of myelinated nerves. The shm mice manifest a progressive neurological phenotype as mice age. We found extensive axonal degeneration and a loss of neurons in the central nervous system and peripheral nervous system in aged shm mice. Axonal alteration of myelinated nerves was defined by abnormal distribution and expression of neurofilaments and derangements in the status of phosphorylated and non/de-phosphorylated neurofilaments. Autophagy-related structures were also accumulated in degenerated axons and neurons. In conclusion, our results suggest that disrupted axon-glia interactions at the paranode cause the cytoskeletal alteration in myelinated axons leading to neuronal cell death, and the process involves detrimental autophagy and aging as factors that promote the pathogenesis.
authors.affiliation: Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. Electronic address: taka@riem.nagoya-u.ac.jp.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Takagishi
authors.affiliation: Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Kimiaki
authors.initials: K
authors.lastname: Katanosaka
authors.affiliation: Research Center for Next-Generation Drug Development, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizoguchi
authors.affiliation: Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
mesh_terms: D000200:Action Potentials; D000375:Aging / Q000473:pathology*; D000818:Animals; D001369:Axons / Q000473:pathology* / Q000502:physiology*; D016923:Cell Death; D066298:In Vitro Techniques; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009410:Nerve Degeneration; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D009457:Neuroglia / Q000473:pathology* / Q000502:physiology*; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D012584:Sciatic Nerve / Q000473:pathology / Q000502:physiology / Q000503:physiopathology
keywords: Autophagy; Motor deficits; Neurodegeneration; Neurofilaments; Nodes of Ranvier; Paranode