Nuclear Accumulation of Histone Deacetylase 4 (HDAC4) Exerts Neurotoxicity in Models of Parkinson’s Disease
Histone deacetylase 4 (HDAC4) is a class II HDAC which is highly expressed in the brain. Previous reports have shown that HDAC4 is essential for normal brain physiology and its deregulation leads to several neurodegenerative disorders. However, it remains unclear whether dysregulation of HDAC4 is sp...
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| Veröffentlicht in: | Molecular neurobiology 2017-11, Vol.54 (9), p.6970-6983 |
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| creator | Wu, Qimei Yang, Xiaoyu Zhang, Lei Zhang, Yu Feng, Linyin |
| description | Histone deacetylase 4 (HDAC4) is a class II HDAC which is highly expressed in the brain. Previous reports have shown that HDAC4 is essential for normal brain physiology and its deregulation leads to several neurodegenerative disorders. However, it remains unclear whether dysregulation of HDAC4 is specifically involved in the development of Parkinson’s disease. In this study, we demonstrate that intracellular trafficking of HDAC4 is important in regulating dopaminergic cell death. While HDAC4 normally localizes to the cytoplasm, nuclear accumulation of HDAC4 was observed in dopaminergic neurons overexpressing A53T mutant α-synuclein treated with MPP
+
/MPTP
in vitro
and
in vivo
. Nuclear-localized HDAC4 repressed cAMP response element-binding protein (CREB) and myocyte enhancer factor 2A (MEF2A), altered neuronal gene expression, and promoted neuronal apoptosis. Furthermore, cytoplasm-to-nucleus shuttling of HDAC4 was determined by its phosphorylation status, which was regulated by PP2A and PKCε. Treatment with PKCε-specific activators, DCP-LA or Bryostatin 1, provided neuroprotection against MPP
+
toxicity in a dose-dependent manner. In summary, our research illustrated that intracellular trafficking of HDAC4 contributes to the vulnerability of cells expressing pathogenic α-synuclein mutants in response to oxidative stress and compounds which maintain cytoplasmic localization of HDAC4 such as PKCε activators that may serve as therapeutic agents for Parkinson’s disease. |
| doi_str_mv | 10.1007/s12035-016-0199-2 |
| format | Article |
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+
/MPTP
in vitro
and
in vivo
. Nuclear-localized HDAC4 repressed cAMP response element-binding protein (CREB) and myocyte enhancer factor 2A (MEF2A), altered neuronal gene expression, and promoted neuronal apoptosis. Furthermore, cytoplasm-to-nucleus shuttling of HDAC4 was determined by its phosphorylation status, which was regulated by PP2A and PKCε. Treatment with PKCε-specific activators, DCP-LA or Bryostatin 1, provided neuroprotection against MPP
+
toxicity in a dose-dependent manner. In summary, our research illustrated that intracellular trafficking of HDAC4 contributes to the vulnerability of cells expressing pathogenic α-synuclein mutants in response to oxidative stress and compounds which maintain cytoplasmic localization of HDAC4 such as PKCε activators that may serve as therapeutic agents for Parkinson’s disease.</description><identifier>ISSN: 0893-7648</identifier><identifier>EISSN: 1559-1182</identifier><identifier>DOI: 10.1007/s12035-016-0199-2</identifier><identifier>PMID: 27785754</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Accumulation ; alpha-Synuclein - genetics ; Animals ; Apoptosis ; Bioaccumulation ; Biomedical and Life Sciences ; Biomedicine ; Brain ; Cell Biology ; Cell death ; Cell Nucleus - drug effects ; Cell Nucleus - enzymology ; Chemical compounds ; Chromatin ; Cyclic AMP response element-binding protein ; Cyclic AMP Response Element-Binding Protein - metabolism ; Cytoplasm ; Deregulation ; Disease Models, Animal ; Dopamine receptors ; Dopaminergic Neurons - drug effects ; Dopaminergic Neurons - metabolism ; Gene expression ; Gene Expression Regulation - drug effects ; Histone deacetylase ; Histone Deacetylases - metabolism ; Humans ; Intracellular ; Localization ; Male ; MEF2 Transcription Factors - metabolism ; Mice, Transgenic ; MPP ; MPTP ; Mutants ; Mutation - genetics ; Neurobiology ; Neurodegenerative diseases ; Neurology ; Neuroprotection ; Neurosciences ; Neurotoxicity ; Neurotoxins - metabolism ; Oxidative stress ; Parkinson Disease - enzymology ; Parkinson Disease - pathology ; Parkinson's disease ; PC12 Cells ; Phosphorylation ; Phosphorylation - drug effects ; Protein kinase C ; Protein Kinase C-epsilon - metabolism ; Protein Kinase Inhibitors - pharmacology ; Proteins ; Rats ; Synuclein ; Toxicity ; Transcription, Genetic - drug effects</subject><ispartof>Molecular neurobiology, 2017-11, Vol.54 (9), p.6970-6983</ispartof><rights>Springer Science+Business Media New York 2016</rights><rights>Molecular Neurobiology is a copyright of Springer, 2017.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-76b0a8d2e7aa249011130d00f289de2a19f337842a7d78bfb7a802ef5c168cf03</citedby><cites>FETCH-LOGICAL-c438t-76b0a8d2e7aa249011130d00f289de2a19f337842a7d78bfb7a802ef5c168cf03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12035-016-0199-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12035-016-0199-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27785754$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Qimei</creatorcontrib><creatorcontrib>Yang, Xiaoyu</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Zhang, Yu</creatorcontrib><creatorcontrib>Feng, Linyin</creatorcontrib><title>Nuclear Accumulation of Histone Deacetylase 4 (HDAC4) Exerts Neurotoxicity in Models of Parkinson’s Disease</title><title>Molecular neurobiology</title><addtitle>Mol Neurobiol</addtitle><addtitle>Mol Neurobiol</addtitle><description>Histone deacetylase 4 (HDAC4) is a class II HDAC which is highly expressed in the brain. Previous reports have shown that HDAC4 is essential for normal brain physiology and its deregulation leads to several neurodegenerative disorders. However, it remains unclear whether dysregulation of HDAC4 is specifically involved in the development of Parkinson’s disease. In this study, we demonstrate that intracellular trafficking of HDAC4 is important in regulating dopaminergic cell death. While HDAC4 normally localizes to the cytoplasm, nuclear accumulation of HDAC4 was observed in dopaminergic neurons overexpressing A53T mutant α-synuclein treated with MPP
+
/MPTP
in vitro
and
in vivo
. Nuclear-localized HDAC4 repressed cAMP response element-binding protein (CREB) and myocyte enhancer factor 2A (MEF2A), altered neuronal gene expression, and promoted neuronal apoptosis. Furthermore, cytoplasm-to-nucleus shuttling of HDAC4 was determined by its phosphorylation status, which was regulated by PP2A and PKCε. Treatment with PKCε-specific activators, DCP-LA or Bryostatin 1, provided neuroprotection against MPP
+
toxicity in a dose-dependent manner. In summary, our research illustrated that intracellular trafficking of HDAC4 contributes to the vulnerability of cells expressing pathogenic α-synuclein mutants in response to oxidative stress and compounds which maintain cytoplasmic localization of HDAC4 such as PKCε activators that may serve as therapeutic agents for Parkinson’s disease.</description><subject>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</subject><subject>Accumulation</subject><subject>alpha-Synuclein - genetics</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Bioaccumulation</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain</subject><subject>Cell Biology</subject><subject>Cell death</subject><subject>Cell Nucleus - drug effects</subject><subject>Cell Nucleus - enzymology</subject><subject>Chemical compounds</subject><subject>Chromatin</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Cyclic AMP Response Element-Binding Protein - metabolism</subject><subject>Cytoplasm</subject><subject>Deregulation</subject><subject>Disease Models, Animal</subject><subject>Dopamine receptors</subject><subject>Dopaminergic Neurons - drug effects</subject><subject>Dopaminergic Neurons - metabolism</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Histone deacetylase</subject><subject>Histone Deacetylases - metabolism</subject><subject>Humans</subject><subject>Intracellular</subject><subject>Localization</subject><subject>Male</subject><subject>MEF2 Transcription Factors - metabolism</subject><subject>Mice, Transgenic</subject><subject>MPP</subject><subject>MPTP</subject><subject>Mutants</subject><subject>Mutation - genetics</subject><subject>Neurobiology</subject><subject>Neurodegenerative diseases</subject><subject>Neurology</subject><subject>Neuroprotection</subject><subject>Neurosciences</subject><subject>Neurotoxicity</subject><subject>Neurotoxins - metabolism</subject><subject>Oxidative stress</subject><subject>Parkinson Disease - enzymology</subject><subject>Parkinson Disease - pathology</subject><subject>Parkinson's disease</subject><subject>PC12 Cells</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Protein kinase C</subject><subject>Protein Kinase C-epsilon - metabolism</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proteins</subject><subject>Rats</subject><subject>Synuclein</subject><subject>Toxicity</subject><subject>Transcription, Genetic - drug effects</subject><issn>0893-7648</issn><issn>1559-1182</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kM1OGzEQx62KCsLHA_RSWeoFDktnbG_sPUYJJUiUcmjPluOdRUs3a2rvSuTW1-jr9UlwFEBcOIzmMP-P0Y-xTwjnCKC_JhQgywJwmqeqCvGBTbAsqwLRiD02AVPJQk-VOWCHKd0DCIGg99mB0NqUulQTtr4ZfUcu8pn343rs3NCGnoeGL9s0hJ74gpynYdO5RFzx0-ViNldn_OKR4pD4DY0xDOGx9e2w4W3Pv4eaurT137r4u-1T6P___Zf4ok2UE47Zx8Z1iU6e9xH79e3i53xZXP-4vJrPrguvpBnyyytwphaknROqAkSUUAM0wlQ1CYdVI6U2Sjhda7NqVtoZENSUHqfGNyCP2Jdd7kMMf0ZKg70PY-xzpcVKKT2VGmVW4U7lY0gpUmMfYrt2cWMR7Baw3QG2GbDdArYiez4_J4-rNdWvjheiWSB2gpRP_R3FN9Xvpj4BUCeF7Q</recordid><startdate>20171101</startdate><enddate>20171101</enddate><creator>Wu, Qimei</creator><creator>Yang, Xiaoyu</creator><creator>Zhang, Lei</creator><creator>Zhang, Yu</creator><creator>Feng, Linyin</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QR</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope></search><sort><creationdate>20171101</creationdate><title>Nuclear Accumulation of Histone Deacetylase 4 (HDAC4) Exerts Neurotoxicity in Models of Parkinson’s Disease</title><author>Wu, Qimei ; Yang, Xiaoyu ; Zhang, Lei ; Zhang, Yu ; Feng, Linyin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-76b0a8d2e7aa249011130d00f289de2a19f337842a7d78bfb7a802ef5c168cf03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</topic><topic>Accumulation</topic><topic>alpha-Synuclein - genetics</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Bioaccumulation</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain</topic><topic>Cell Biology</topic><topic>Cell death</topic><topic>Cell Nucleus - drug effects</topic><topic>Cell Nucleus - enzymology</topic><topic>Chemical compounds</topic><topic>Chromatin</topic><topic>Cyclic AMP response element-binding protein</topic><topic>Cyclic AMP Response Element-Binding Protein - metabolism</topic><topic>Cytoplasm</topic><topic>Deregulation</topic><topic>Disease Models, Animal</topic><topic>Dopamine receptors</topic><topic>Dopaminergic Neurons - drug effects</topic><topic>Dopaminergic Neurons - metabolism</topic><topic>Gene expression</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Histone deacetylase</topic><topic>Histone Deacetylases - metabolism</topic><topic>Humans</topic><topic>Intracellular</topic><topic>Localization</topic><topic>Male</topic><topic>MEF2 Transcription Factors - metabolism</topic><topic>Mice, Transgenic</topic><topic>MPP</topic><topic>MPTP</topic><topic>Mutants</topic><topic>Mutation - genetics</topic><topic>Neurobiology</topic><topic>Neurodegenerative diseases</topic><topic>Neurology</topic><topic>Neuroprotection</topic><topic>Neurosciences</topic><topic>Neurotoxicity</topic><topic>Neurotoxins - metabolism</topic><topic>Oxidative stress</topic><topic>Parkinson Disease - enzymology</topic><topic>Parkinson Disease - pathology</topic><topic>Parkinson's disease</topic><topic>PC12 Cells</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Protein kinase C</topic><topic>Protein Kinase C-epsilon - metabolism</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proteins</topic><topic>Rats</topic><topic>Synuclein</topic><topic>Toxicity</topic><topic>Transcription, Genetic - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Qimei</creatorcontrib><creatorcontrib>Yang, Xiaoyu</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Zhang, Yu</creatorcontrib><creatorcontrib>Feng, Linyin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Psychology Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><jtitle>Molecular neurobiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Qimei</au><au>Yang, Xiaoyu</au><au>Zhang, Lei</au><au>Zhang, Yu</au><au>Feng, Linyin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nuclear Accumulation of Histone Deacetylase 4 (HDAC4) Exerts Neurotoxicity in Models of Parkinson’s Disease</atitle><jtitle>Molecular neurobiology</jtitle><stitle>Mol Neurobiol</stitle><addtitle>Mol Neurobiol</addtitle><date>2017-11-01</date><risdate>2017</risdate><volume>54</volume><issue>9</issue><spage>6970</spage><epage>6983</epage><pages>6970-6983</pages><issn>0893-7648</issn><eissn>1559-1182</eissn><abstract>Histone deacetylase 4 (HDAC4) is a class II HDAC which is highly expressed in the brain. Previous reports have shown that HDAC4 is essential for normal brain physiology and its deregulation leads to several neurodegenerative disorders. However, it remains unclear whether dysregulation of HDAC4 is specifically involved in the development of Parkinson’s disease. In this study, we demonstrate that intracellular trafficking of HDAC4 is important in regulating dopaminergic cell death. While HDAC4 normally localizes to the cytoplasm, nuclear accumulation of HDAC4 was observed in dopaminergic neurons overexpressing A53T mutant α-synuclein treated with MPP
+
/MPTP
in vitro
and
in vivo
. Nuclear-localized HDAC4 repressed cAMP response element-binding protein (CREB) and myocyte enhancer factor 2A (MEF2A), altered neuronal gene expression, and promoted neuronal apoptosis. Furthermore, cytoplasm-to-nucleus shuttling of HDAC4 was determined by its phosphorylation status, which was regulated by PP2A and PKCε. Treatment with PKCε-specific activators, DCP-LA or Bryostatin 1, provided neuroprotection against MPP
+
toxicity in a dose-dependent manner. In summary, our research illustrated that intracellular trafficking of HDAC4 contributes to the vulnerability of cells expressing pathogenic α-synuclein mutants in response to oxidative stress and compounds which maintain cytoplasmic localization of HDAC4 such as PKCε activators that may serve as therapeutic agents for Parkinson’s disease.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>27785754</pmid><doi>10.1007/s12035-016-0199-2</doi><tpages>14</tpages></addata></record> |
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| ispartof | Molecular neurobiology, 2017-11, Vol.54 (9), p.6970-6983 |
| issn | 0893-7648 1559-1182 |
| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Accumulation alpha-Synuclein - genetics Animals Apoptosis Bioaccumulation Biomedical and Life Sciences Biomedicine Brain Cell Biology Cell death Cell Nucleus - drug effects Cell Nucleus - enzymology Chemical compounds Chromatin Cyclic AMP response element-binding protein Cyclic AMP Response Element-Binding Protein - metabolism Cytoplasm Deregulation Disease Models, Animal Dopamine receptors Dopaminergic Neurons - drug effects Dopaminergic Neurons - metabolism Gene expression Gene Expression Regulation - drug effects Histone deacetylase Histone Deacetylases - metabolism Humans Intracellular Localization Male MEF2 Transcription Factors - metabolism Mice, Transgenic MPP MPTP Mutants Mutation - genetics Neurobiology Neurodegenerative diseases Neurology Neuroprotection Neurosciences Neurotoxicity Neurotoxins - metabolism Oxidative stress Parkinson Disease - enzymology Parkinson Disease - pathology Parkinson's disease PC12 Cells Phosphorylation Phosphorylation - drug effects Protein kinase C Protein Kinase C-epsilon - metabolism Protein Kinase Inhibitors - pharmacology Proteins Rats Synuclein Toxicity Transcription, Genetic - drug effects |
| title | Nuclear Accumulation of Histone Deacetylase 4 (HDAC4) Exerts Neurotoxicity in Models of Parkinson’s Disease |
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