title: Axonopathy is associated with complex axonal transport defects in a model of multiple sclerosis.
abstract: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized by myelin and axonal pathology. In a viral model of MS, we tested whether axonopathy initiation and development are based on an impaired transport of neurofilaments. Spinal cords of Theiler's murine encephalomyelitis virus (TMEV)-infected and mock-infected mice and TMEV infected neuroblastoma N1E-115 cells were analyzed by microarray analysis, light microscopy and electron and laser confocal microscopy. In vivo axonal accumulation of non-phosphorylated neurofilaments after TMEV infection revealed a temporal development caused by the impairments of the axonal traffic consisting of the downregulation of kinesin family member 5A, dynein cytoplasmic heavy chain 1, tau-1 and β-tubulin III expression. In addition, alterations of the protein metabolism were also noticed. In vitro, the TMEV-infected N1E-115 cells developed tandem-repeated swellings similar to in vivo alterations. Furthermore, the hypothesis of an underlying axonal self-destruction program involving nicotinamide adenine dinucleotide depletion was supported by molecular findings. The obtained data indicate that neurofilament accumulation in TME is mainly the result of dysregulation of their axonal transport machinery and impairment of neurofilament phosphorylation and protein metabolism. The present findings allow a more precise understanding of the complex interactions responsible for initiation and development of axonopathies in inflammatory degenerative diseases.
authors: Department of Pathology, University of Veterinary Medicine, Hannover, Germany.
authors: Mihaela
authors: M
authors: Kreutzer
authors: Frauke
authors: F
authors: Seehusen
authors: Robert
authors: R
authors: Kreutzer
authors: Kidsadagorn
authors: K
authors: Pringproa
authors: Maren
authors: M
authors: Kummerfeld
authors: Peter
authors: P
authors: Claus
authors: Ulrich
authors: U
authors: Deschl
authors: Arno
authors: A
authors: Kalkul
authors: Andreas
authors: A
authors: Beineke
authors: Wolfgang
authors: W
authors: Baumgärtner
authors: Reiner
authors: R
authors: Ulrich
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D018188:Cardiovirus Infections / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D051379:Mice; D046228:Microarray Analysis; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D016900:Neurofilament Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology*; D017945:Theilovirus
chemical_list: D016900:Neurofilament Proteins