Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity.
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.
Leng
Yan
Y
Molecular Neurobiology Section, Biological Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA.
Chuang
De-Maw
DM
D000107:Acetylation; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D018692:Antimanic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism* / Q000633:toxicity; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044763:Ubiquitin-Conjugating Enzymes / Q000096:biosynthesis; D014635:Valproic Acid / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics
D000927:Anticonvulsants; D018692:Antimanic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; D016376:Oligonucleotides, Antisense; D010654:Phenylbutyrates; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051844:alpha-Synuclein; D018698:Glutamic Acid; C012589:trichostatin A; D014635:Valproic Acid; C075773:4-phenylbutyric acid; D044763:Ubiquitin-Conjugating Enzymes