PT  - JOURNAL ARTICLE
AU  - Yan Leng
AU  - De-Maw Chuang
TI  - Endogenous α-Synuclein Is Induced by Valproic Acid through Histone Deacetylase Inhibition and Participates in Neuroprotection against Glutamate-Induced Excitotoxicity
AID  - 10.1523/JNEUROSCI.0096-06.2006
DP  - 2006 Jul 12
TA  - The Journal of Neuroscience
PG  - 7502--7512
VI  - 26
IP  - 28
4099  - http://www.jneurosci.org/content/26/28/7502.short
4100  - http://www.jneurosci.org/content/26/28/7502.full
SO  - J. Neurosci.2006 Jul 12; 26
AB  - Emerging evidence suggests that α-synuclein (α-syn), which is traditionally thought to have a pathophysiological role in neurodegenerative diseases, can have neuroprotective effects. This study aimed to investigate whether endogenous α-syn in neurons can be induced by valproic acid (VPA), a mood-stabilizer, anticonvulsant and histone deacetylase (HDAC) inhibitor, and if so, whether the α-syn induction is neuroprotective. VPA treatment of rat cerebellar granule cells caused a robust dose- and time-dependent increase in levels of α-syn protein and mRNA and in the intensity of α-syn immunostaining. Knockdown of VPA-induced α-syn overexpression with α-syn antisense oligonucleotides or siRNA completely blocked VPA-induced neuroprotection. α-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 α-syn by VPA was associated with inhibition of HDAC activity, resulting in hyperacetylation of histone H3 in the α-syn promoter and a marked increase in α-syn promoter activity. Moreover, VPA-induced α-syn induction and neuroprotection were mimicked by HDAC inhibitors sodium 4-phenylbutyrate and trichostatin A (TSA). α-syn was also induced by VPA in rat cerebral cortical neurons. Additionally, treatment of rats with VPA, sodium butyrate, or TSA markedly increased α-syn protein levels in the cortex and cerebellum. Together, our results demonstrate for the first time that VPA induces α-syn in neurons through inhibition of HDAC and that this α-syn induction is critically involved in neuroprotection against glutamate excitotoxicity. Clinically, VPA may represent a suitable treatment for excitotoxicity-related neurodegenerative diseases.