RGD Reference Report - Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity. - Rat Genome Database

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Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity.

Authors: Leng, Yan  Chuang, De-Maw 
Citation: Leng Y and Chuang DM, J Neurosci. 2006 Jul 12;26(28):7502-12. doi: 10.1523/JNEUROSCI.0096-06.2006.
RGD ID: 13506279
Pubmed: PMID:16837598   (View Abstract at PubMed)
PMCID: PMC6674182   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.0096-06.2006   (Journal Full-text)

Emerging evidence suggests that alpha-synuclein (alpha-syn), which is traditionally thought to have a pathophysiological role in neurodegenerative diseases, can have neuroprotective effects. This study aimed to investigate whether endogenous alpha-syn in neurons can be induced by valproic acid (VPA), a mood-stabilizer, anticonvulsant and histone deacetylase (HDAC) inhibitor, and if so, whether the alpha-syn induction is neuroprotective. VPA treatment of rat cerebellar granule cells caused a robust dose- and time-dependent increase in levels of alpha-syn protein and mRNA and in the intensity of alpha-syn immunostaining. Knockdown of VPA-induced alpha-syn overexpression with alpha-syn antisense oligonucleotides or siRNA completely blocked VPA-induced neuroprotection. alpha-Syn knockdown also exacerbated glutamate neurotoxicity, stimulated the expression of the proapoptotic gene ubiquitin-conjugating enzyme E2N, and downregulated the expression of the anti-apoptotic gene Bcl-2. Induction of alpha-syn by VPA was associated with inhibition of HDAC activity, resulting in hyperacetylation of histone H3 in the alpha-syn promoter and a marked increase in alpha-syn promoter activity. Moreover, VPA-induced alpha-syn induction and neuroprotection were mimicked by HDAC inhibitors sodium 4-phenylbutyrate and trichostatin A (TSA). alpha-syn was also induced by VPA in rat cerebral cortical neurons. Additionally, treatment of rats with VPA, sodium butyrate, or TSA markedly increased alpha-syn protein levels in the cortex and cerebellum. Together, our results demonstrate for the first time that VPA induces alpha-syn in neurons through inhibition of HDAC and that this alpha-syn induction is critically involved in neuroprotection against glutamate excitotoxicity. Clinically, VPA may represent a suitable treatment for excitotoxicity-related neurodegenerative diseases.



Gene-Chemical Interaction Annotations    
valproic acid  (EXP,ISO)

Molecular Pathway Annotations    
Phenotype Annotations    

Mammalian Phenotype
Objects Annotated

Genes (Rattus norvegicus)
Snca  (synuclein alpha)

Genes (Mus musculus)
Snca  (synuclein, alpha)

Genes (Homo sapiens)
SNCA  (synuclein alpha)


Additional Information