Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery
Feng Mei,
Klaus Lehmann-Horn,
Yun-An A Shen,
Kelsey A Rankin,
Karin J Stebbins,
Daniel S Lorrain,
Kara Pekarek,
Sharon A Sagan,
Lan Xiao,
Cory Teuscher,
H-Christian von Büdingen,
Jürgen Wess,
J Josh Lawrence,
Ari J Green,
Stephen PJ Fancy,
Scott S Zamvil,
Jonah R Chan
Affiliations
Feng Mei
Department of Neurology, University of California, San Francisco, San Francisco, United States; Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, China
Klaus Lehmann-Horn
Department of Neurology, University of California, San Francisco, San Francisco, United States
Yun-An A Shen
Department of Neurology, University of California, San Francisco, San Francisco, United States
Kelsey A Rankin
Department of Neurology, University of California, San Francisco, San Francisco, United States
Karin J Stebbins
Inception Sciences, San Diego, United States
Daniel S Lorrain
Inception Sciences, San Diego, United States
Kara Pekarek
Department of Neurology, University of California, San Francisco, San Francisco, United States
Sharon A Sagan
Department of Neurology, University of California, San Francisco, San Francisco, United States
Lan Xiao
Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, China
Cory Teuscher
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States
H-Christian von Büdingen
Department of Neurology, University of California, San Francisco, San Francisco, United States
Jürgen Wess
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States
J Josh Lawrence
Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, School of Medicine, Lubbock, United States
Ari J Green
Department of Neurology, University of California, San Francisco, San Francisco, United States
Stephen PJ Fancy
Department of Neurology, University of California, San Francisco, San Francisco, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States
Scott S Zamvil
Department of Neurology, University of California, San Francisco, San Francisco, United States
Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination. Demonstrating the functional significance of remyelination necessitates selectively altering the timing of remyelination relative to inflammation and degeneration. We demonstrate accelerated remyelination after EAE induction by direct lineage analysis and hypothesize that newly formed myelin remains stable at the height of inflammation due in part to the absence of MOG expression in immature myelin. Oligodendroglial-specific genetic ablation of the M1 muscarinic receptor, a potent negative regulator of oligodendrocyte differentiation and myelination, results in accelerated remyelination, preventing axonal loss and improving functional recovery. Together our findings demonstrate that accelerated remyelination supports axonal integrity and neuronal function after inflammatory demyelination.
