(CMT 2B) The mood stabilizer valproic acid improves defective neurite formation

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J Neurosci Res. 2010 Jul 19.

The mood stabilizer valproic acid improves defective neurite formation caused by

charcot-marie-tooth disease-associated mutant Rab7 through the JNK signaling

pathway.

Yamauchi J, Torii T, Kusakawa S, Sanbe A, Nakamura K, Takashima S, Hamasaki H,

Kawaguchi S, Miyamoto Y, Tanoue A.

Department of Pharmacology, National Research Institute for Child Health and

Development, Setagaya, Tokyo, Japan.

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.