PMID:16837598

Citation	Leng, Y and Chuang, DM (2006) Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity. J. Neurosci. 26:7502-12
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.
Links	PubMed Online version:10.1523/JNEUROSCI.0096-06.2006
Keywords	Acetylation; Animals; Anticonvulsants/pharmacology; Antimanic Agents/pharmacology; Cells, Cultured; Cerebellum/cytology; Cerebellum/metabolism; Cerebral Cortex/cytology; Cerebral Cortex/metabolism; Glutamic Acid/metabolism; Glutamic Acid/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; alpha-Synuclein/genetics
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:SYUA	involved_in	GO:1901215: negative regulation of neuron death	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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