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PMID: 16837598 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

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

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 26 ·No. 28 ·2006-07-12 ·Pages 7502-12

Leng Y, Chuang DM

Abstract

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.

MeSH Terms
Acetylation Animals Anticonvulsants/pharmacology Antimanic Agents/pharmacology Cells, Cultured Cerebellum/cytology,metabolism Cerebral Cortex/cytology,metabolism Glutamic Acid/metabolism,toxicity Histone Deacetylase Inhibitors Histones/metabolism Hydroxamic Acids/pharmacology Neuroprotective Agents/pharmacology Oligonucleotides, Antisense/pharmacology Phenylbutyrates/pharmacology Promoter Regions, Genetic Proto-Oncogene Proteins c-bcl-2/biosynthesis RNA, Small Interfering/genetics Rats Rats, Sprague-Dawley Ubiquitin-Conjugating Enzymes/biosynthesis Valproic Acid/pharmacology alpha-Synuclein/biosynthesis,genetics
Chemicals
Anticonvulsants Antimanic Agents Histone Deacetylase Inhibitors Histones Hydroxamic Acids Neuroprotective Agents Oligonucleotides, Antisense Phenylbutyrates Proto-Oncogene Proteins c-bcl-2 RNA, Small Interfering alpha-Synuclein Glutamic Acid trichostatin A Valproic Acid 4-phenylbutyric acid Ubiquitin-Conjugating Enzymes
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Leng Yan
Molecular Neurobiology Section, Biological Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA.
Chuang De-Maw
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.0096-06.2006
Published
2006-07-12
Pages
7502-12
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6674182
Subset
IM
Grants
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.0096-06.2006 PMC Full Text View journal details
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