Overexpression of an inactive mutant cathepsin D increases endogenous alpha-synuclein and cathepsin B activity in SH-SY5Y cells*
Identifieur interne : 000613 ( Pmc/Curation ); précédent : 000612; suivant : 000614Overexpression of an inactive mutant cathepsin D increases endogenous alpha-synuclein and cathepsin B activity in SH-SY5Y cells*
Auteurs : Donna Crabtree ; Matthew Dodson ; Xiaosen Ouyang ; Michaël Boyer-Guittaut [France] ; Qiuli Liang ; Mary E. Ballestas ; Naomi Fineberg ; Jianhua ZhangSource :
- Journal of neurochemistry [ 0022-3042 ] ; 2013.
Abstract
Parkinson’s disease (PD) is a neurodegenerative movement disorder. The histopathology of PD comprises proteinaceous inclusions known as
Url:
DOI: 10.1111/jnc.12497
PubMed: 24138030
PubMed Central: 3951679
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Donna Crabtree<affiliation><nlm:aff id="A1">Department of Pathology, University of Alabama at Birmingham</nlm:aff>
<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A1">Department of Pathology, University of Alabama at Birmingham</nlm:aff>
<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Center for Free Radical Biology, University of Alabama at Birmingham</nlm:aff>
<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Center for Free Radical Biology, University of Alabama at Birmingham</nlm:aff>
<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A1">Department of Pathology, University of Alabama at Birmingham</nlm:aff>
<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Center for Free Radical Biology, University of Alabama at Birmingham</nlm:aff>
<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A3">Department of Veterans Affairs, Birmingham VA Medical Center</nlm:aff>
<wicri:noCountry code="subfield">Birmingham VA Medical Center</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Center for Free Radical Biology, University of Alabama at Birmingham</nlm:aff>
<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A3">Department of Veterans Affairs, Birmingham VA Medical Center</nlm:aff>
<wicri:noCountry code="subfield">Birmingham VA Medical Center</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A3">Department of Veterans Affairs, Birmingham VA Medical Center</nlm:aff>
<wicri:noCountry code="subfield">Birmingham VA Medical Center</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A1">Department of Pathology, University of Alabama at Birmingham</nlm:aff>
<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Center for Free Radical Biology, University of Alabama at Birmingham</nlm:aff>
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</affiliation>
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<country xml:lang="fr">France</country>
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<country xml:lang="fr">France</country>
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</affiliation>
<affiliation><nlm:aff id="A1">Department of Pathology, University of Alabama at Birmingham</nlm:aff>
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</affiliation>
<affiliation><nlm:aff id="A3">Department of Veterans Affairs, Birmingham VA Medical Center</nlm:aff>
<wicri:noCountry code="subfield">Birmingham VA Medical Center</wicri:noCountry>
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<affiliation><nlm:aff id="A5">Department of Biostatistics, UAB School of Public Health</nlm:aff>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Overexpression of an inactive mutant cathepsin D increases endogenous alpha-synuclein and cathepsin B activity in SH-SY5Y cells<sup>*</sup>
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<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
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<author><name sortKey="Dodson, Matthew" sort="Dodson, Matthew" uniqKey="Dodson M" first="Matthew" last="Dodson">Matthew Dodson</name>
<affiliation><nlm:aff id="A1">Department of Pathology, University of Alabama at Birmingham</nlm:aff>
<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Center for Free Radical Biology, University of Alabama at Birmingham</nlm:aff>
<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Ouyang, Xiaosen" sort="Ouyang, Xiaosen" uniqKey="Ouyang X" first="Xiaosen" last="Ouyang">Xiaosen Ouyang</name>
<affiliation><nlm:aff id="A1">Department of Pathology, University of Alabama at Birmingham</nlm:aff>
<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
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<affiliation><nlm:aff id="A2">Center for Free Radical Biology, University of Alabama at Birmingham</nlm:aff>
<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A3">Department of Veterans Affairs, Birmingham VA Medical Center</nlm:aff>
<wicri:noCountry code="subfield">Birmingham VA Medical Center</wicri:noCountry>
</affiliation>
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<author><name sortKey="Boyer Guittaut, Michael" sort="Boyer Guittaut, Michael" uniqKey="Boyer Guittaut M" first="Michaël" last="Boyer-Guittaut">Michaël Boyer-Guittaut</name>
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<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
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<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
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<author><name sortKey="Liang, Qiuli" sort="Liang, Qiuli" uniqKey="Liang Q" first="Qiuli" last="Liang">Qiuli Liang</name>
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<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
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<wicri:noCountry code="subfield">University of Alabama at Birmingham</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A3">Department of Veterans Affairs, Birmingham VA Medical Center</nlm:aff>
<wicri:noCountry code="subfield">Birmingham VA Medical Center</wicri:noCountry>
</affiliation>
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<author><name sortKey="Ballestas, Mary E" sort="Ballestas, Mary E" uniqKey="Ballestas M" first="Mary E." last="Ballestas">Mary E. Ballestas</name>
<affiliation><nlm:aff id="A4">Department of Pediatrics, UAB School of Public Health</nlm:aff>
<wicri:noCountry code="subfield">UAB School of Public Health</wicri:noCountry>
</affiliation>
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<author><name sortKey="Fineberg, Naomi" sort="Fineberg, Naomi" uniqKey="Fineberg N" first="Naomi" last="Fineberg">Naomi Fineberg</name>
<affiliation><nlm:aff id="A5">Department of Biostatistics, UAB School of Public Health</nlm:aff>
<wicri:noCountry code="subfield">UAB School of Public Health</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhang, Jianhua" sort="Zhang, Jianhua" uniqKey="Zhang J" first="Jianhua" last="Zhang">Jianhua Zhang</name>
<affiliation><nlm:aff id="A1">Department of Pathology, University of Alabama at Birmingham</nlm:aff>
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<series><title level="j">Journal of neurochemistry</title>
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<front><div type="abstract" xml:lang="en"><p id="P1">Parkinson’s disease (PD) is a neurodegenerative movement disorder. The histopathology of PD comprises proteinaceous inclusions known as <italic>Lewy bodies,</italic>
which contains aggregated α-synuclein. Cathepsin D (CD) is a lysosomal protease previously demonstrated to cleave α-synuclein and decrease its toxicity in both cell lines and mouse brains <italic>in vivo.</italic>
Here we show that pharmacological inhibition of CD, or introduction of catalytically inactive mutant CD resulted in decreased CD activity and increased cathepsin B activity, suggesting a possible compensatory response to inhibition of CD activity. However, this increased cathepsin B activity was not sufficient to maintain α-synuclein degradation, as evidenced by the accumulation of endogenous α-synuclein. Interestingly, the levels of LC3, LAMP1 and LAMP2, proteins involved in autophagy-lysosomal activities, as well as total lysosomal mass as assessed by LysoTracker flow cytometry, were unchanged. Neither autophagic flux nor proteasomal activities differ between cells over expressing wildtype versus mutant CD. These observations point to a critical regulatory role for that endogenous CD activity in dopaminergic cells in α-synuclein homeostasis which cannot be compensated for by increased Cathepsin B. These data support the potential need to enhance CD function in order to attenuate α-synuclein accumulation as a therapeutic strategy against development of synucleinopathy.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">2985190R</journal-id>
<journal-id journal-id-type="pubmed-jr-id">5004</journal-id>
<journal-id journal-id-type="nlm-ta">J Neurochem</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Neurochem.</journal-id>
<journal-title-group><journal-title>Journal of neurochemistry</journal-title>
</journal-title-group>
<issn pub-type="ppub">0022-3042</issn>
<issn pub-type="epub">1471-4159</issn>
</journal-meta>
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<article-id pub-id-type="doi">10.1111/jnc.12497</article-id>
<article-id pub-id-type="manuscript">NIHMS536540</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Overexpression of an inactive mutant cathepsin D increases endogenous alpha-synuclein and cathepsin B activity in SH-SY5Y cells<sup>*</sup>
</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Crabtree</surname>
<given-names>Donna</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dodson</surname>
<given-names>Matthew</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ouyang</surname>
<given-names>Xiaosen</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Boyer-Guittaut</surname>
<given-names>Michaël</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liang</surname>
<given-names>Qiuli</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ballestas</surname>
<given-names>Mary E.</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fineberg</surname>
<given-names>Naomi</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Jianhua</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Department of Pathology, University of Alabama at Birmingham</aff>
<aff id="A2"><label>2</label>
Center for Free Radical Biology, University of Alabama at Birmingham</aff>
<aff id="A3"><label>3</label>
Department of Veterans Affairs, Birmingham VA Medical Center</aff>
<aff id="A4"><label>4</label>
Department of Pediatrics, UAB School of Public Health</aff>
<aff id="A5"><label>5</label>
Department of Biostatistics, UAB School of Public Health</aff>
<aff id="A6"><label>6</label>
Université de Franche-Comté, Laboratoire de Biochimie, EA3922, Estrogènes, Expression Génique et Pathologies du Système Nerveux Central, SFR IBCT, U.F.R. Sciences et Techniques, 16 route de Gray, 25030 Besançon Cedex, France</aff>
<author-notes><corresp id="FN1">To whom correspondence should be addressed: Jianhua Zhang, Ph.D., Department of Pathology, University of Alabama at Birmingham, BMRII-534, 901 19<sup>th</sup>
Street S, Birmingham, AL 35294, USA, Phone: 205-996-5153; Fax: 205-934-7447; <email>zhanja@uab.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>9</day>
<month>12</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>13</day>
<month>11</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="ppub"><month>3</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>3</month>
<year>2015</year>
</pub-date>
<volume>128</volume>
<issue>6</issue>
<fpage>950</fpage>
<lpage>961</lpage>
<pmc-comment>elocation-id from pubmed: 10.1111/jnc.12497</pmc-comment>
<abstract><p id="P1">Parkinson’s disease (PD) is a neurodegenerative movement disorder. The histopathology of PD comprises proteinaceous inclusions known as <italic>Lewy bodies,</italic>
which contains aggregated α-synuclein. Cathepsin D (CD) is a lysosomal protease previously demonstrated to cleave α-synuclein and decrease its toxicity in both cell lines and mouse brains <italic>in vivo.</italic>
Here we show that pharmacological inhibition of CD, or introduction of catalytically inactive mutant CD resulted in decreased CD activity and increased cathepsin B activity, suggesting a possible compensatory response to inhibition of CD activity. However, this increased cathepsin B activity was not sufficient to maintain α-synuclein degradation, as evidenced by the accumulation of endogenous α-synuclein. Interestingly, the levels of LC3, LAMP1 and LAMP2, proteins involved in autophagy-lysosomal activities, as well as total lysosomal mass as assessed by LysoTracker flow cytometry, were unchanged. Neither autophagic flux nor proteasomal activities differ between cells over expressing wildtype versus mutant CD. These observations point to a critical regulatory role for that endogenous CD activity in dopaminergic cells in α-synuclein homeostasis which cannot be compensated for by increased Cathepsin B. These data support the potential need to enhance CD function in order to attenuate α-synuclein accumulation as a therapeutic strategy against development of synucleinopathy.</p>
</abstract>
<kwd-group><kwd>cathepsin D</kwd>
<kwd>α-synuclein</kwd>
<kwd>autophagy</kwd>
<kwd>lysosome</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
</record>
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