Lethal adulthood myelin breakdown by oligodendrocyte-specific Ddx54 knockout
Hiroaki Oizumi,
Yuki Miyamoto,
Chika Seiwa,
Masahiro Yamamoto,
Nozomu Yoshioka,
Seiichi Iizuka,
Tomohiro Torii,
Katsuya Ohbuchi,
Kazushige Mizoguchi,
Junji Yamauchi,
Hiroaki Asou
Affiliations
Hiroaki Oizumi
Tsumura Kampo Laboratories, Tsumura & Co, Ami, Ibaraki 300-1192, Japan
Yuki Miyamoto
Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo 157-8535, Japan; Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
Chika Seiwa
Glovia Myelin Research Institute, Tsurumi-ku, Yokohama, Kanagawa 230-0046, Japan
Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-ku, Niigata 951-8510, Japan
Seiichi Iizuka
Tsumura Kampo Laboratories, Tsumura & Co, Ami, Ibaraki 300-1192, Japan
Tomohiro Torii
Laboratory of Ion Channel Pathophysiology, Graduate School of Brain Science, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan
Katsuya Ohbuchi
Tsumura Kampo Laboratories, Tsumura & Co, Ami, Ibaraki 300-1192, Japan
Kazushige Mizoguchi
Tsumura Kampo Laboratories, Tsumura & Co, Ami, Ibaraki 300-1192, Japan
Junji Yamauchi
Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo 157-8535, Japan; Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
Hiroaki Asou
Glovia Myelin Research Institute, Tsurumi-ku, Yokohama, Kanagawa 230-0046, Japan
Summary: Multiple sclerosis (MS) is a leading disease that causes disability in young adults. We have previously shown that a DEAD-box RNA helicase Ddx54 binds to mRNA and protein isoforms of myelin basic protein (MBP) and that Ddx54 siRNA blocking abrogates oligodendrocyte migration and myelination. Herein, we show that MBP-driven Ddx54 knockout mice (Ddx54 fl/fl;MBP-Cre), after the completion of normal postnatal myelination, gradually develop abnormalities in behavioral profiles and learning ability, inner myelin sheath breakdown, loss of myelinated axons, apoptosis of oligodendrocytes, astrocyte and microglia activation, and they die within 7 months but show minimal peripheral immune cell infiltration. Myelin in Ddx54fl/fl;MBP-Cre is highly vulnerable to the neurotoxicant cuprizone and Ddx54 knockdown greatly impairs myelination in vitro. Ddx54 expression in oligodendrocyte-lineage cells decreased in corpus callosum of MS patients. Our results demonstrate that Ddx54 is indispensable for myelin homeostasis, and they provide a demyelinating disease model based on intrinsic disintegration of adult myelin.
