title: The mood stabilizer valproic acid improves defective neurite formation caused by Charcot-Marie-Tooth disease-associated mutant Rab7 through the JNK signaling pathway.
abstract: Charcot-Marie-Tooth (CMT) disease is the most frequent peripheral neuropathy affecting the Schwann cells and neurons. CMT disease type 2 (CMT2) neuropathies are characterized by peripheral nerve aberrance. Four missense mutations of Rab7, a small GTPase of the Rab family involved in intracellular vesicular trafficking, are associated with the CMT2B phenotype. Despite a growing body of evidence concerning the gene structures responsible for genetically heterogenous CMT2B and other CMT2 neuropathies, little is known about the in vitro neuropathy model and how CMT2B-associated mutation-caused aberrant neuritogenesis is properly reversed. Here, we show that valproic acid (VPA), a classical mood-stabilizing drug, improves defective neurite formation in N1E-115 neuroblastoma cells regardless of which CMT2B-associated Rab7 mutant protein is expressed. The effect is mediated by c-Jun N-terminal kinase (JNK) signaling, but not by deacetylase inhibition activity of VPA itself. Furthermore, VPA has similar effects in dorsal root ganglion (DRG) neurons expressing any of the four mutant Rab7 proteins. Thus, VPA has a previously unknown potential to improve defective neuritogenesis associated with CMT2B in vitro, indicating that JNK should be a potential therapeutic target for treatments aimed at improving neuritogenesis.
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan. jyamauchi@nch.go.jp
authors.forename: Junji
authors.initials: J
authors.lastname: Yamauchi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Torii
authors.forename: Shinji
authors.initials: S
authors.lastname: Kusakawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nakamura
authors.forename: Shou
authors.initials: S
authors.lastname: Takashima
authors.forename: Hajime
authors.initials: H
authors.lastname: Hamasaki
authors.forename: Shogo
authors.initials: S
authors.lastname: Kawaguchi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Akito
authors.initials: A
authors.lastname: Tanoue
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000502:physiology; D000090802:rab7 GTP-Binding Proteins
chemical_list: D018696:Neuroprotective Agents; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; C000716466:rab7 GTP-binding proteins, rat; D014635:Valproic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D020691:rab GTP-Binding Proteins