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The Journal of Neuroscience, July 12, 2006, 26(28):7502-7512; doi:10.1523/JNEUROSCI.0096-06.2006

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Cellular/Molecular
Endogenous -Synuclein Is Induced by Valproic Acid through Histone Deacetylase Inhibition and Participates in Neuroprotection against Glutamate-Induced Excitotoxicity

Yan Leng and De-Maw Chuang

Molecular Neurobiology Section, Biological Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363

Correspondence should be addressed to Dr. De-Maw Chuang, Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Building 10, Room 4C206, 10 Center Drive, MSC 1363, Bethesda, MD 20892-1363. Email: chuang{at}mail.nih.gov

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

Key words: -synuclein; valproate; neuroprotection; excitotoxicity; histone deacetylase; Parkinson’s disease

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Received Jan. 28, 2005; revised May 2, 2006; accepted June 11, 2006.

Correspondence should be addressed to Dr. De-Maw Chuang, Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Building 10, Room 4C206, 10 Center Drive, MSC 1363, Bethesda, MD 20892-1363. Email: chuang{at}mail.nih.gov

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