Journal
JOURNAL OF NEUROSCIENCE RESEARCH
Volume 88, Issue 14, Pages 3189-3197Publisher
WILEY
DOI: 10.1002/jnr.22460
Keywords
CMT2B; Rab7; VPA; JNK; neuritogenesis
Categories
Funding
- Japanese Ministry of Education, Culture, Sports, Science, and Technology
- Japanese Ministry of Health, Labor, and Welfare
- Astellas Metabolic Disease Foundation
- Fuji Foundation for Protein Research
- Mochida Foundation
- Japanese Society for the Promotion of Science for Young Scientists
- Japan Health Sciences Foundation
- Kanae Foundation
- Kato Memorial Bioscience Foundation
- Naito Foundation
- Novartis Foundation
- Suzuken Memorial Foundation
- Takeda Science Foundation
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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. (c) 2010 Wiley-Liss, Inc.
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