Protective role of olesoxime against wild-type α-synuclein-induced toxicity in human neuronally differentiated SHSY-5Y cells
Identifieur interne : 000432 ( Pmc/Curation ); précédent : 000431; suivant : 000433Protective role of olesoxime against wild-type α-synuclein-induced toxicity in human neuronally differentiated SHSY-5Y cells
Auteurs : C. Gouarné [France] ; J. Tracz [France] ; M Giraudon Paoli [France] ; V. Deluca [France] ; M. Seimandi [France] ; G. Tardif [France] ; M. Xilouri [Grèce] ; L. Stefanis [Grèce] ; T. Bordet [France] ; R M Pruss [France]Source :
- British Journal of Pharmacology [ 0007-1188 ] ; 2014.
Abstract
Parkinson's disease (PD) is usually diagnosed clinically from classical motor symptoms, while definitive diagnosis is made postmortem, based on the presence of Lewy bodies and nigral neuron cell loss. α-Synuclein (ASYN), the main protein component of Lewy bodies, clearly plays a role in the neurodegeneration that characterizes PD. Additionally, mutation in the
We used here a novel, mechanistically approachable and attractive cellular model based on the inducible overexpression of human wild-type ASYN in neuronally differentiated human neuroblastoma (SHSY-5Y) cells. This model demonstrates gradual cellular degeneration, coinciding temporally with the appearance of soluble and membrane-bound ASYN oligomers and cell death combining both apoptotic and non-apoptotic pathways.
Olesoxime fully protected differentiated SHSY-5Y cells from cell death, neurite retraction and cytoplasmic shrinkage induced by moderate ASYN overexpression. This protection was associated with a reduction in cytochrome c release from mitochondria and caspase-9 activation suggesting that olesoxime prevented ASYN toxicity by preserving mitochondrial integrity and function. In addition, olesoxime displayed neurotrophic effects on neuronally differentiated SHSY-5Y cells, independent of ASYN expression, by promoting their differentiation.
Because ASYN is a common underlying factor in many cases of PD, olesoxime could be a promising therapy to slow neurodegeneration in PD.
Url:
DOI: 10.1111/bph.12939
PubMed: 25220617
PubMed Central: 4280980
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<front><div type="abstract" xml:lang="en"><sec><title>BACKGROUND AND PURPOSE</title>
<p>Parkinson's disease (PD) is usually diagnosed clinically from classical motor symptoms, while definitive diagnosis is made postmortem, based on the presence of Lewy bodies and nigral neuron cell loss. α-Synuclein (ASYN), the main protein component of Lewy bodies, clearly plays a role in the neurodegeneration that characterizes PD. Additionally, mutation in the <italic>SNCA</italic>
gene or copy number variations are associated with some forms of familial PD. Here, the objective of the study was to evaluate whether olesoxime, a promising neuroprotective drug can prevent ASYN-mediated neurotoxicity.</p>
</sec>
<sec><title>EXPERIMENTAL APPROACH</title>
<p>We used here a novel, mechanistically approachable and attractive cellular model based on the inducible overexpression of human wild-type ASYN in neuronally differentiated human neuroblastoma (SHSY-5Y) cells. This model demonstrates gradual cellular degeneration, coinciding temporally with the appearance of soluble and membrane-bound ASYN oligomers and cell death combining both apoptotic and non-apoptotic pathways.</p>
</sec>
<sec><title>KEY RESULTS</title>
<p>Olesoxime fully protected differentiated SHSY-5Y cells from cell death, neurite retraction and cytoplasmic shrinkage induced by moderate ASYN overexpression. This protection was associated with a reduction in cytochrome c release from mitochondria and caspase-9 activation suggesting that olesoxime prevented ASYN toxicity by preserving mitochondrial integrity and function. In addition, olesoxime displayed neurotrophic effects on neuronally differentiated SHSY-5Y cells, independent of ASYN expression, by promoting their differentiation.</p>
</sec>
<sec><title>CONCLUSIONS AND IMPLICATIONS</title>
<p>Because ASYN is a common underlying factor in many cases of PD, olesoxime could be a promising therapy to slow neurodegeneration in PD.</p>
</sec>
</div>
</front>
</TEI>
<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>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Br J Pharmacol</journal-id>
<journal-id journal-id-type="iso-abbrev">Br. J. Pharmacol</journal-id>
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<article-categories><subj-group subj-group-type="heading"><subject>Research Papers</subject>
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<title-group><article-title>Protective role of olesoxime against wild-type α-synuclein-induced toxicity in human neuronally differentiated SHSY-5Y cells</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Gouarné</surname>
<given-names>C</given-names>
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</name>
<xref ref-type="aff" rid="au1">1</xref>
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<contrib contrib-type="author"><name><surname>Paoli</surname>
<given-names>M Giraudon</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Deluca</surname>
<given-names>V</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
</contrib>
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<given-names>M</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tardif</surname>
<given-names>G</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
</contrib>
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<given-names>M</given-names>
</name>
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</contrib>
<contrib contrib-type="author"><name><surname>Stefanis</surname>
<given-names>L</given-names>
</name>
<xref ref-type="aff" rid="au2">2</xref>
<xref ref-type="aff" rid="au3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bordet</surname>
<given-names>T</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
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<contrib contrib-type="author"><name><surname>Pruss</surname>
<given-names>R M</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
</contrib>
<aff id="au1"><label>1</label>
<institution>Trophos, Parc Scientifique de Luminy, Luminy Biotech Entreprises</institution>
<addr-line>Marseille, France</addr-line>
</aff>
<aff id="au2"><label>2</label>
<institution>Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens</institution>
<addr-line>Athens, Greece</addr-line>
</aff>
<aff id="au3"><label>3</label>
<institution>Second Department of Neurology, University of Athens Medical School</institution>
<addr-line>Athens, Greece</addr-line>
</aff>
</contrib-group>
<author-notes><corresp id="cor1">Caroline Gouarné, Trophos, Parc Scientifique de Luminy, Luminy Biotech Enterprises, Case 931, 13288 Marseille Cedex 9, France. E-mail: <email>cgouarne@trophos.com</email>
</corresp>
<fn id="fn1" fn-type="present-address"><label>*</label>
<p>Present address: Biotherapies Institute for Rare Diseases, 1 Rue de l'Internationale, Evry 91002, France.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>1</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>01</day>
<month>12</month>
<year>2014</year>
</pub-date>
<volume>172</volume>
<issue>1</issue>
<fpage>235</fpage>
<lpage>245</lpage>
<history><date date-type="received"><day>02</day>
<month>4</month>
<year>2014</year>
</date>
<date date-type="rev-recd"><day>04</day>
<month>9</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>08</day>
<month>9</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© 2014 The British Pharmacological Society</copyright-statement>
<copyright-year>2014</copyright-year>
</permissions>
<abstract><sec><title>BACKGROUND AND PURPOSE</title>
<p>Parkinson's disease (PD) is usually diagnosed clinically from classical motor symptoms, while definitive diagnosis is made postmortem, based on the presence of Lewy bodies and nigral neuron cell loss. α-Synuclein (ASYN), the main protein component of Lewy bodies, clearly plays a role in the neurodegeneration that characterizes PD. Additionally, mutation in the <italic>SNCA</italic>
gene or copy number variations are associated with some forms of familial PD. Here, the objective of the study was to evaluate whether olesoxime, a promising neuroprotective drug can prevent ASYN-mediated neurotoxicity.</p>
</sec>
<sec><title>EXPERIMENTAL APPROACH</title>
<p>We used here a novel, mechanistically approachable and attractive cellular model based on the inducible overexpression of human wild-type ASYN in neuronally differentiated human neuroblastoma (SHSY-5Y) cells. This model demonstrates gradual cellular degeneration, coinciding temporally with the appearance of soluble and membrane-bound ASYN oligomers and cell death combining both apoptotic and non-apoptotic pathways.</p>
</sec>
<sec><title>KEY RESULTS</title>
<p>Olesoxime fully protected differentiated SHSY-5Y cells from cell death, neurite retraction and cytoplasmic shrinkage induced by moderate ASYN overexpression. This protection was associated with a reduction in cytochrome c release from mitochondria and caspase-9 activation suggesting that olesoxime prevented ASYN toxicity by preserving mitochondrial integrity and function. In addition, olesoxime displayed neurotrophic effects on neuronally differentiated SHSY-5Y cells, independent of ASYN expression, by promoting their differentiation.</p>
</sec>
<sec><title>CONCLUSIONS AND IMPLICATIONS</title>
<p>Because ASYN is a common underlying factor in many cases of PD, olesoxime could be a promising therapy to slow neurodegeneration in PD.</p>
</sec>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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