The mood stabilizer valproic acid improves defective neurite formation caused by charcot‐marie‐tooth disease‐associated mutant Rab7 through the JNK signaling pathway

Yamauchi, Junji; Torii, Tomohiro; Kusakawa, Shinji; Sanbe, Atsushi; Nakamura, Kazuaki; Takashima, Shou; Hamasaki, Hajime; Kawaguchi, Shogo; Miyamoto, Yuki; Tanoue, Akito

doi:10.1002/jnr.22460

Cited by 45 publications

(42 citation statements)

References 51 publications

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“…RAB7 controls specific neuronal functions such as NTF (neurotrophin) trafficking and signaling and it is responsible for retrograde axonal traffic, neurite outgrowth and neuronal migration, 20–24 besides interacting with and regulating assembly of 2 intermediate filament proteins, VIM (vimentin) and PRPH (peripherin), which are involved in neurite outgrowth and axonal regeneration. 25–31 Neuronal functions are highly dependent on protein synthesis and degradation, and a constitutive autophagic flux is fundamental for a number of key neuronal processes.…”

Section: Introductionmentioning

confidence: 99%

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

et al. 2018

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Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by 5 mutations in the RAB7A gene, a ubiquitously expressed GTPase controlling late endocytic trafficking. In neurons, RAB7A also controls neuronal-specific processes such as NTF (neurotrophin) trafficking and signaling, neurite outgrowth and neuronal migration. Given the involvement of macroautophagy/autophagy in several neurodegenerative diseases and considering that RAB7A is fundamental for autophagosome maturation, we investigated whether CMT2B-causing mutants affect the ability of this gene to regulate autophagy. In HeLa cells, we observed a reduced localization of all CMT2B-causing RAB7A mutants on autophagic compartments. Furthermore, compared to expression of RAB7AWT, expression of these mutants caused a reduced autophagic flux, similar to what happens in cells expressing the dominant negative RAB7AT22N mutant. Consistently, both basal and starvation-induced autophagy were strongly inhibited in skin fibroblasts from a CMT2B patient carrying the RAB7AV162M mutation, suggesting that alteration of the autophagic flux could be responsible for neurodegeneration.

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Section: Introductionmentioning

confidence: 99%

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

et al. 2018

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“…For instance, valproate stimulates neurite growth in cells including primary cultured hippocampal neurons (Natori et al, 2008), SH-SY5Y cells (Yuan et al, 2001), N1E-115 neuroblastoma cells (Yamauchi et al, 2007) and PC12 cells (van Bergeijk et al, 2006). More importantly, valproic acid spreads axonal regeneration in animal models of optic nerve crush (Biermann et al, 2010), sciatic nerve axotomy (Cui et al, 2003), as well as Charcot-Marie-Tooth disease (Yamauchi et al, 2010). In addition, it inhibits the collapse of sensory neuron growth cones and increases growth cone area (Williams et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Valproic acid improves locomotion in vivo after SCI and axonal growth of neurons in vitro

Han

Sun

et al. 2012

Experimental Neurology

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Previous studies have found that valproic acid (VPA), a histone deacetylases (HDAC) inhibitor, improves outcomes in a rat model of spinal cord injury (SCI). The study here aimed to further illuminate the neuroprotective effects of VPA against SCI, both in vivo and in vitro. First, spinal cord injury was performed in rats using NYU impactor. Delayed VPA injection (8 h following SCI) significantly accelerated locomotor recovery. VPA therapy also suppressed SCI-induced hypoacetylation of histone and promoted expressions of BDNF and GDNF. Next, the influence of VPA on axonal growth inhibited by a myelin protein was tested. Neurons from embryonic spinal cord or hippocampus were cultured on plates coated with Nogo-A peptide, and escalating concentrations of VPA were added into the cultures. VPA treatment, in a concentration dependent manner, allowed neurons to overcome Nogo-A inhibition of neurite outgrowth. Meanwhile, VPA exposure increased the level of histone acetylation and expression of BDNF in spinal neurons. Cumulatively, these findings indicate that VPA is possibly a promising medication and deserves translational trials for spinal cord injury.

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“…Mutations in Rab7 lead to altered neurotrophin traffic and impaired translocation of activated ERK1/2 (extracellularsignal-regulated kinase 1/2) [22,23,25]. However, expression of disease-causing mutant Rab7 proteins inhibits neurite outgrowth in several different cell lines also independently of NGF stimulation, indicating that other alternative Trkindependent pathways are also affected by these mutant proteins [26,27].…”

Section: Rab7 and The Nervous Systemmentioning

confidence: 96%

Molecular basis of Charcot–Marie–Tooth type 2B disease

Bucci

Luca

2012

Biochemical Society Transactions

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CMT2B (Charcot-Marie-Tooth type 2B) disease is an autosomal dominant peripheral neuropathy whose onset is in the second or third decade of life, thus in adolescence or young adulthood. CMT2B is clinically characterized by severe symmetric distal sensory loss, reduced tendon reflexes at ankles, weakness in the lower limbs and muscle atrophy, complicated by ulcerations that often lead to amputations. Four missense mutations in the gene encoding the small GTPase Rab7 cause the CMT2B neuropathy. Rab7 is a ubiquitous protein that regulates transport to late endosomes and lysosomes in the endocytic pathway. In neurons, Rab7 is important for endosomal trafficking and signalling of neurotrophins, and for retrograde axonal transport. Recent data on CMT2B-causing Rab7 mutant proteins show that these proteins exhibit altered koff rates and, as a consequence, they are mainly in the GTP-bound state and bind more strongly to Rab7 effector proteins. Notably, expression of CMT2B-causing Rab7 mutant proteins strongly inhibit neurite outgrowth in several cells lines and alter NGF (nerve growth factor) trafficking and signalling. These data indicate that Rab7 plays an essential role in neuronal cells and that CMT2B-causing Rab7 mutant proteins alter neuronal specific pathways, but do not fully explain why only peripheral neurons are affected in CMT2B. In the present paper, we discuss the current understanding of the molecular and cellular mechanisms underlying CMT2B, and we consider possible hypotheses in order to explain how alterations of Rab7 function lead to CMT2B.

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The mood stabilizer valproic acid improves defective neurite formation caused by charcot‐marie‐tooth disease‐associated mutant Rab7 through the JNK signaling pathway

Cited by 45 publications

References 51 publications

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

Valproic acid improves locomotion in vivo after SCI and axonal growth of neurons in vitro

Molecular basis of Charcot–Marie–Tooth type 2B disease

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