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β-synuclein modulates α-synuclein neurotoxicity by reducing α-synuclein protein expression
Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of alpha-synuclein in characteristic inclusions known as "Lewy bodies". As mutations altering alpha-synuclein structure or increasing alpha-synuclein expression level can cause familial form...
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| Published in: | Human molecular genetics 2006-10, Vol.15 (20), p.3002-3011 |
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| container_end_page | 3011 |
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| container_title | Human molecular genetics |
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| creator | YUXIN FAN LIMPRASERT, Pornprot MURRAY, Ian V. J SMITH, Annette C LEE, Virginia M.-Y TROJANOWSKI, John Q SOPHER, Bryce L LA SPADA, Albert R |
| description | Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of alpha-synuclein in characteristic inclusions known as "Lewy bodies". As mutations altering alpha-synuclein structure or increasing alpha-synuclein expression level can cause familial forms of PD or related Lewy body disorders, alpha-synuclein is believed to play a central role in the process of neuron toxicity, degeneration and death in "synucleinopathies". beta-synuclein is closely related to alpha-synuclein and has been shown to inhibit alpha-synuclein aggregation and ameliorate alpha-synuclein neurotoxicity. We generated beta-synuclein transgenic mice and observed a marked reduction in alpha-synuclein protein expression in the cortex of mice over-expressing beta-synuclein. This reduction in alpha-synuclein protein expression was not accompanied by decreases in alpha-synuclein mRNA expression. Using the prion protein promoter alpha-synuclein A53T mouse model of PD, we demonstrated that over-expression of beta-synuclein could retard the progression of impaired motor performance, reduce alpha-synuclein aggregation and extend survival in doubly transgenic mice. We attributed the amelioration of alpha-synuclein neurotoxicity in such bigenic mice to the ability of beta-synuclein to reduce alpha-synuclein protein expression based upon I(125) autoradiography quantification. Our findings indicate that increased expression of beta-synuclein protein results in a reduction of alpha-synuclein protein expression. As increased expression of alpha-synuclein may cause or contribute to PD pathogenesis in sporadic and familial forms of disease, this observation has important implications for the development of therapies for PD. |
| doi_str_mv | 10.1093/hmg/ddl242 |
| format | article |
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J ; SMITH, Annette C ; LEE, Virginia M.-Y ; TROJANOWSKI, John Q ; SOPHER, Bryce L ; LA SPADA, Albert R</creator><creatorcontrib>YUXIN FAN ; LIMPRASERT, Pornprot ; MURRAY, Ian V. J ; SMITH, Annette C ; LEE, Virginia M.-Y ; TROJANOWSKI, John Q ; SOPHER, Bryce L ; LA SPADA, Albert R</creatorcontrib><description>Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of alpha-synuclein in characteristic inclusions known as "Lewy bodies". As mutations altering alpha-synuclein structure or increasing alpha-synuclein expression level can cause familial forms of PD or related Lewy body disorders, alpha-synuclein is believed to play a central role in the process of neuron toxicity, degeneration and death in "synucleinopathies". beta-synuclein is closely related to alpha-synuclein and has been shown to inhibit alpha-synuclein aggregation and ameliorate alpha-synuclein neurotoxicity. We generated beta-synuclein transgenic mice and observed a marked reduction in alpha-synuclein protein expression in the cortex of mice over-expressing beta-synuclein. This reduction in alpha-synuclein protein expression was not accompanied by decreases in alpha-synuclein mRNA expression. Using the prion protein promoter alpha-synuclein A53T mouse model of PD, we demonstrated that over-expression of beta-synuclein could retard the progression of impaired motor performance, reduce alpha-synuclein aggregation and extend survival in doubly transgenic mice. We attributed the amelioration of alpha-synuclein neurotoxicity in such bigenic mice to the ability of beta-synuclein to reduce alpha-synuclein protein expression based upon I(125) autoradiography quantification. Our findings indicate that increased expression of beta-synuclein protein results in a reduction of alpha-synuclein protein expression. As increased expression of alpha-synuclein may cause or contribute to PD pathogenesis in sporadic and familial forms of disease, this observation has important implications for the development of therapies for PD.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddl242</identifier><identifier>PMID: 16959793</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>alpha-Synuclein - metabolism ; Animals ; beta-Synuclein - genetics ; beta-Synuclein - metabolism ; Biological and medical sciences ; Fundamental and applied biological sciences. Psychology ; Genetics of eukaryotes. Biological and molecular evolution ; Humans ; Mice ; Mice, Transgenic ; Molecular and cellular biology ; Parkinson Disease - metabolism ; Parkinson Disease - physiopathology ; Parkinson Disease - psychology ; Prions - genetics</subject><ispartof>Human molecular genetics, 2006-10, Vol.15 (20), p.3002-3011</ispartof><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c382t-2cad6ffe3086b9acc4b357f6679137b968ae9670889e523805919791cb12ad0d3</citedby><cites>FETCH-LOGICAL-c382t-2cad6ffe3086b9acc4b357f6679137b968ae9670889e523805919791cb12ad0d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18224387$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16959793$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>YUXIN FAN</creatorcontrib><creatorcontrib>LIMPRASERT, Pornprot</creatorcontrib><creatorcontrib>MURRAY, Ian V. J</creatorcontrib><creatorcontrib>SMITH, Annette C</creatorcontrib><creatorcontrib>LEE, Virginia M.-Y</creatorcontrib><creatorcontrib>TROJANOWSKI, John Q</creatorcontrib><creatorcontrib>SOPHER, Bryce L</creatorcontrib><creatorcontrib>LA SPADA, Albert R</creatorcontrib><title>β-synuclein modulates α-synuclein neurotoxicity by reducing α-synuclein protein expression</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of alpha-synuclein in characteristic inclusions known as "Lewy bodies". As mutations altering alpha-synuclein structure or increasing alpha-synuclein expression level can cause familial forms of PD or related Lewy body disorders, alpha-synuclein is believed to play a central role in the process of neuron toxicity, degeneration and death in "synucleinopathies". beta-synuclein is closely related to alpha-synuclein and has been shown to inhibit alpha-synuclein aggregation and ameliorate alpha-synuclein neurotoxicity. We generated beta-synuclein transgenic mice and observed a marked reduction in alpha-synuclein protein expression in the cortex of mice over-expressing beta-synuclein. This reduction in alpha-synuclein protein expression was not accompanied by decreases in alpha-synuclein mRNA expression. Using the prion protein promoter alpha-synuclein A53T mouse model of PD, we demonstrated that over-expression of beta-synuclein could retard the progression of impaired motor performance, reduce alpha-synuclein aggregation and extend survival in doubly transgenic mice. We attributed the amelioration of alpha-synuclein neurotoxicity in such bigenic mice to the ability of beta-synuclein to reduce alpha-synuclein protein expression based upon I(125) autoradiography quantification. Our findings indicate that increased expression of beta-synuclein protein results in a reduction of alpha-synuclein protein expression. As increased expression of alpha-synuclein may cause or contribute to PD pathogenesis in sporadic and familial forms of disease, this observation has important implications for the development of therapies for PD.</description><subject>alpha-Synuclein - metabolism</subject><subject>Animals</subject><subject>beta-Synuclein - genetics</subject><subject>beta-Synuclein - metabolism</subject><subject>Biological and medical sciences</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Molecular and cellular biology</subject><subject>Parkinson Disease - metabolism</subject><subject>Parkinson Disease - physiopathology</subject><subject>Parkinson Disease - psychology</subject><subject>Prions - genetics</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><recordid>eNpV0MtKxDAUBuAgijOObnwA6UYXQp2TpM1lKYM3ENzoUkqapGOklzFpYfpY-iDzTHaYwujqwOHj5-dH6BzDDQZJ5x_Vcm5MSRJygKY4YRATEPQQTUGyJGYS2ASdhPAJgFlC-TGaYCZTySWdovfNTxz6utOldXVUNaYrVWtDtPn-865t55u2WTvt2j7K-8hb02lXL_-z1YC2165X3obgmvoUHRWqDPZsvDP0dn_3uniMn18enha3z7GmgrQx0cqworAUBMul0jrJacoLxrjElOeSCWUl4yCEtCmhAlKJh_pY55goA4bO0NUud6jw1dnQZpUL2palqm3ThYxAmnBOYIDXO6h9E4K3RbbyrlK-zzBk2zGzYcxsN-aAL8bULq-s2dNxvQFcjkAFrcrCq1q7sHeCkIQKTn8BxTeBmw</recordid><startdate>20061015</startdate><enddate>20061015</enddate><creator>YUXIN FAN</creator><creator>LIMPRASERT, Pornprot</creator><creator>MURRAY, Ian V. 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Biological and molecular evolution</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Molecular and cellular biology</topic><topic>Parkinson Disease - metabolism</topic><topic>Parkinson Disease - physiopathology</topic><topic>Parkinson Disease - psychology</topic><topic>Prions - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>YUXIN FAN</creatorcontrib><creatorcontrib>LIMPRASERT, Pornprot</creatorcontrib><creatorcontrib>MURRAY, Ian V. 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J</au><au>SMITH, Annette C</au><au>LEE, Virginia M.-Y</au><au>TROJANOWSKI, John Q</au><au>SOPHER, Bryce L</au><au>LA SPADA, Albert R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>β-synuclein modulates α-synuclein neurotoxicity by reducing α-synuclein protein expression</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2006-10-15</date><risdate>2006</risdate><volume>15</volume><issue>20</issue><spage>3002</spage><epage>3011</epage><pages>3002-3011</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of alpha-synuclein in characteristic inclusions known as "Lewy bodies". As mutations altering alpha-synuclein structure or increasing alpha-synuclein expression level can cause familial forms of PD or related Lewy body disorders, alpha-synuclein is believed to play a central role in the process of neuron toxicity, degeneration and death in "synucleinopathies". beta-synuclein is closely related to alpha-synuclein and has been shown to inhibit alpha-synuclein aggregation and ameliorate alpha-synuclein neurotoxicity. We generated beta-synuclein transgenic mice and observed a marked reduction in alpha-synuclein protein expression in the cortex of mice over-expressing beta-synuclein. This reduction in alpha-synuclein protein expression was not accompanied by decreases in alpha-synuclein mRNA expression. Using the prion protein promoter alpha-synuclein A53T mouse model of PD, we demonstrated that over-expression of beta-synuclein could retard the progression of impaired motor performance, reduce alpha-synuclein aggregation and extend survival in doubly transgenic mice. We attributed the amelioration of alpha-synuclein neurotoxicity in such bigenic mice to the ability of beta-synuclein to reduce alpha-synuclein protein expression based upon I(125) autoradiography quantification. Our findings indicate that increased expression of beta-synuclein protein results in a reduction of alpha-synuclein protein expression. As increased expression of alpha-synuclein may cause or contribute to PD pathogenesis in sporadic and familial forms of disease, this observation has important implications for the development of therapies for PD.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>16959793</pmid><doi>10.1093/hmg/ddl242</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | AUTh Library subscriptions: Oxford University Press |
| subjects | alpha-Synuclein - metabolism Animals beta-Synuclein - genetics beta-Synuclein - metabolism Biological and medical sciences Fundamental and applied biological sciences. Psychology Genetics of eukaryotes. Biological and molecular evolution Humans Mice Mice, Transgenic Molecular and cellular biology Parkinson Disease - metabolism Parkinson Disease - physiopathology Parkinson Disease - psychology Prions - genetics |
| title | β-synuclein modulates α-synuclein neurotoxicity by reducing α-synuclein protein expression |
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