A pilot trial of the microtubule-interacting peptide (NAP) in mice overexpressing alpha-synuclein shows improvement in motor function and reduction of alpha-synuclein inclusions
Identifieur interne : 000A72 ( Pmc/Checkpoint ); précédent : 000A71; suivant : 000A73A pilot trial of the microtubule-interacting peptide (NAP) in mice overexpressing alpha-synuclein shows improvement in motor function and reduction of alpha-synuclein inclusions
Auteurs : Sheila M. Fleming ; Caitlin K. Mulligan ; Franziska Richter ; Farzad Mortazavi ; Vincent Lemesre ; Carmen Frias ; Chunni Zhu ; Alistair Stewart ; Illana Gozes ; Bruce Morimoto ; Marie-Françoise ChesseletSource :
- Molecular and cellular neurosciences [ 1044-7431 ] ; 2010.
Abstract
Abnormal accumulation of α-synuclein is associated with several neurodegenerative disorders (synucleinopathies), including sporadic Parkinson’s disease (PD). Genetic mutations and multiplication of α-synuclein cause familial forms of PD and polymorphisms in the α-synuclein gene are associated with PD risk. Overexpression of α-synuclein can impair essential functions within the cell such as microtubule-dependent transport, suggesting that compounds that act on the microtubule system may have therapeutic benefit for synucleinopathies. In this study, mice overexpressing human wildtype α-synuclein under the Thy1 promoter (Thy1-aSyn) and littermate wildtype control mice were administered daily the microtubule-interacting peptide NAPVSIPQ (NAP; also known as davunetide or AL-108) intranasally for two months starting at one month of age, in a regimen known to produce effective concentrations of the peptide in mouse brain. Motor performance, coordination, and activity were assessed at the end of treatment. Olfactory function, which is altered in PD, was measured one month later. Mice were sacrificed at 4.5 months of age, and their brains examined for proteinase K-resistant α-synuclein inclusions in the substantia nigra and olfactory bulb. NAP-treated Thy1-aSyn mice showed a 38% decrease in the number of errors per step in the challenging beam traversal test and a reduction in proteinase K-resistant α-synuclein inclusions in the substantia nigra compared to vehicle treated transgenics. The data indicate a significant behavioral benefit and a long lasting improvement of α-synuclein pathology following administration of a short term (2 month) NAP administration in a mouse model of synucleinopathy.
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DOI: 10.1016/j.mcn.2010.12.011
PubMed: 21193046
PubMed Central: 3046337
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Fleming</name></author><author><name sortKey="Mulligan, Caitlin K" sort="Mulligan, Caitlin K" uniqKey="Mulligan C" first="Caitlin K." last="Mulligan">Caitlin K. Mulligan</name></author><author><name sortKey="Richter, Franziska" sort="Richter, Franziska" uniqKey="Richter F" first="Franziska" last="Richter">Franziska Richter</name></author><author><name sortKey="Mortazavi, Farzad" sort="Mortazavi, Farzad" uniqKey="Mortazavi F" first="Farzad" last="Mortazavi">Farzad Mortazavi</name></author><author><name sortKey="Lemesre, Vincent" sort="Lemesre, Vincent" uniqKey="Lemesre V" first="Vincent" last="Lemesre">Vincent Lemesre</name></author><author><name sortKey="Frias, Carmen" sort="Frias, Carmen" uniqKey="Frias C" first="Carmen" last="Frias">Carmen Frias</name></author><author><name sortKey="Zhu, Chunni" sort="Zhu, Chunni" uniqKey="Zhu C" first="Chunni" last="Zhu">Chunni Zhu</name></author><author><name sortKey="Stewart, Alistair" sort="Stewart, Alistair" uniqKey="Stewart A" first="Alistair" last="Stewart">Alistair Stewart</name></author><author><name sortKey="Gozes, Illana" sort="Gozes, Illana" uniqKey="Gozes I" first="Illana" last="Gozes">Illana Gozes</name></author><author><name sortKey="Morimoto, Bruce" sort="Morimoto, Bruce" uniqKey="Morimoto B" first="Bruce" last="Morimoto">Bruce Morimoto</name></author><author><name sortKey="Chesselet, Marie Francoise" sort="Chesselet, Marie Francoise" uniqKey="Chesselet M" first="Marie-Françoise" last="Chesselet">Marie-Françoise Chesselet</name></author></analytic><series><title level="j">Molecular and cellular neurosciences</title><idno type="ISSN">1044-7431</idno><idno type="eISSN">1095-9327</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">Abnormal accumulation of α-synuclein is associated with several neurodegenerative disorders (synucleinopathies), including sporadic Parkinson’s disease (PD). Genetic mutations and multiplication of α-synuclein cause familial forms of PD and polymorphisms in the α-synuclein gene are associated with PD risk. Overexpression of α-synuclein can impair essential functions within the cell such as microtubule-dependent transport, suggesting that compounds that act on the microtubule system may have therapeutic benefit for synucleinopathies. In this study, mice overexpressing human wildtype α-synuclein under the Thy1 promoter (Thy1-aSyn) and littermate wildtype control mice were administered daily the microtubule-interacting peptide NAPVSIPQ (NAP; also known as davunetide or AL-108) intranasally for two months starting at one month of age, in a regimen known to produce effective concentrations of the peptide in mouse brain. Motor performance, coordination, and activity were assessed at the end of treatment. Olfactory function, which is altered in PD, was measured one month later. Mice were sacrificed at 4.5 months of age, and their brains examined for proteinase K-resistant α-synuclein inclusions in the substantia nigra and olfactory bulb. NAP-treated Thy1-aSyn mice showed a 38% decrease in the number of errors per step in the challenging beam traversal test and a reduction in proteinase K-resistant α-synuclein inclusions in the substantia nigra compared to vehicle treated transgenics. The data indicate a significant behavioral benefit and a long lasting improvement of α-synuclein pathology following administration of a short term (2 month) NAP administration in a mouse model of synucleinopathy.</p></div></front></TEI><pmc article-type="research-article" xml:lang="EN"><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">9100095</journal-id><journal-id journal-id-type="pubmed-jr-id">8509</journal-id><journal-id journal-id-type="nlm-ta">Mol Cell Neurosci</journal-id><journal-title>Molecular and cellular neurosciences</journal-title><issn pub-type="ppub">1044-7431</issn><issn pub-type="epub">1095-9327</issn></journal-meta><article-meta><article-id pub-id-type="pmid">21193046</article-id><article-id pub-id-type="pmc">3046337</article-id><article-id pub-id-type="doi">10.1016/j.mcn.2010.12.011</article-id><article-id pub-id-type="manuscript">NIHMS261400</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>A pilot trial of the microtubule-interacting peptide (NAP) in mice overexpressing alpha-synuclein shows improvement in motor function and reduction of alpha-synuclein inclusions</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Fleming</surname><given-names>Sheila M.</given-names></name><aff id="A1">Departments of Neurology and Neurobiology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA</aff></contrib><contrib contrib-type="author"><name><surname>Mulligan</surname><given-names>Caitlin K.</given-names></name><aff id="A2">Departments of Neurology and Neurobiology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA</aff></contrib><contrib contrib-type="author"><name><surname>Richter</surname><given-names>Franziska</given-names></name><aff id="A3">Departments of Neurology and Neurobiology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA</aff></contrib><contrib contrib-type="author"><name><surname>Mortazavi</surname><given-names>Farzad</given-names></name><aff id="A4">Departments of Neurology and Neurobiology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA</aff></contrib><contrib contrib-type="author"><name><surname>Lemesre</surname><given-names>Vincent</given-names></name><aff id="A5">Departments of Neurology and Neurobiology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA</aff></contrib><contrib contrib-type="author"><name><surname>Frias</surname><given-names>Carmen</given-names></name><aff id="A6">Departments of Neurology and Neurobiology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA</aff></contrib><contrib contrib-type="author"><name><surname>Zhu</surname><given-names>Chunni</given-names></name><aff id="A7">Departments of Neurology and Neurobiology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA</aff></contrib><contrib contrib-type="author"><name><surname>Stewart</surname><given-names>Alistair</given-names></name><aff id="A8">Allon Therapeutics Inc. Vancouver BC V6B 2S2, Canada</aff></contrib><contrib contrib-type="author"><name><surname>Gozes</surname><given-names>Illana</given-names></name><aff id="A9">Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Allon Therapeutics Inc. Vancouver BC V6B 2S2, Canada</aff></contrib><contrib contrib-type="author"><name><surname>Morimoto</surname><given-names>Bruce</given-names></name><aff id="A10">Allon Therapeutics Inc. Vancouver BC V6B 2S2, Canada</aff></contrib><contrib contrib-type="author"><name><surname>Chesselet</surname><given-names>Marie-Françoise</given-names></name><aff id="A11">Departments of Neurology and Neurobiology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA</aff></contrib></contrib-group><author-notes><corresp id="CR1"><bold>Correspondence</bold>: Marie-Françoise Chesselet, M.D., Ph.D., Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, 310-267-1782, 310-267-1786 (fax), <email>mchesselet@mednet.ucla.edu</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>3</day><month>1</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>27</day><month>12</month><year>2010</year></pub-date><pub-date pub-type="ppub"><month>3</month><year>2011</year></pub-date><pub-date pub-type="pmc-release"><day>1</day><month>3</month><year>2012</year></pub-date><volume>46</volume><issue>3</issue><fpage>597</fpage><lpage>606</lpage><permissions><copyright-statement>© 2010 Elsevier Inc. All rights reserved.</copyright-statement><copyright-year>2010</copyright-year></permissions><abstract><p id="P1">Abnormal accumulation of α-synuclein is associated with several neurodegenerative disorders (synucleinopathies), including sporadic Parkinson’s disease (PD). Genetic mutations and multiplication of α-synuclein cause familial forms of PD and polymorphisms in the α-synuclein gene are associated with PD risk. Overexpression of α-synuclein can impair essential functions within the cell such as microtubule-dependent transport, suggesting that compounds that act on the microtubule system may have therapeutic benefit for synucleinopathies. In this study, mice overexpressing human wildtype α-synuclein under the Thy1 promoter (Thy1-aSyn) and littermate wildtype control mice were administered daily the microtubule-interacting peptide NAPVSIPQ (NAP; also known as davunetide or AL-108) intranasally for two months starting at one month of age, in a regimen known to produce effective concentrations of the peptide in mouse brain. Motor performance, coordination, and activity were assessed at the end of treatment. Olfactory function, which is altered in PD, was measured one month later. Mice were sacrificed at 4.5 months of age, and their brains examined for proteinase K-resistant α-synuclein inclusions in the substantia nigra and olfactory bulb. NAP-treated Thy1-aSyn mice showed a 38% decrease in the number of errors per step in the challenging beam traversal test and a reduction in proteinase K-resistant α-synuclein inclusions in the substantia nigra compared to vehicle treated transgenics. The data indicate a significant behavioral benefit and a long lasting improvement of α-synuclein pathology following administration of a short term (2 month) NAP administration in a mouse model of synucleinopathy.</p></abstract><contract-num rid="ES1">U54 ES012078-05
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||ES</contract-num><contract-sponsor id="ES1">National Institute of Environmental Health Sciences : NIEHS</contract-sponsor><contract-sponsor id="NS1">National Institute of Neurological Disorders and Stroke : NINDS</contract-sponsor></article-meta></front></pmc><affiliations><list></list><tree><noCountry><name sortKey="Chesselet, Marie Francoise" sort="Chesselet, Marie Francoise" uniqKey="Chesselet M" first="Marie-Françoise" last="Chesselet">Marie-Françoise Chesselet</name><name sortKey="Fleming, Sheila M" sort="Fleming, Sheila M" uniqKey="Fleming S" first="Sheila M." last="Fleming">Sheila M. Fleming</name><name sortKey="Frias, Carmen" sort="Frias, Carmen" uniqKey="Frias C" first="Carmen" last="Frias">Carmen Frias</name><name sortKey="Gozes, Illana" sort="Gozes, Illana" uniqKey="Gozes I" first="Illana" last="Gozes">Illana Gozes</name><name sortKey="Lemesre, Vincent" sort="Lemesre, Vincent" uniqKey="Lemesre V" first="Vincent" last="Lemesre">Vincent Lemesre</name><name sortKey="Morimoto, Bruce" sort="Morimoto, Bruce" uniqKey="Morimoto B" first="Bruce" last="Morimoto">Bruce Morimoto</name><name sortKey="Mortazavi, Farzad" sort="Mortazavi, Farzad" uniqKey="Mortazavi F" first="Farzad" last="Mortazavi">Farzad Mortazavi</name><name sortKey="Mulligan, Caitlin K" sort="Mulligan, Caitlin K" uniqKey="Mulligan C" first="Caitlin K." last="Mulligan">Caitlin K. Mulligan</name><name sortKey="Richter, Franziska" sort="Richter, Franziska" uniqKey="Richter F" first="Franziska" last="Richter">Franziska Richter</name><name sortKey="Stewart, Alistair" sort="Stewart, Alistair" uniqKey="Stewart A" first="Alistair" last="Stewart">Alistair Stewart</name><name sortKey="Zhu, Chunni" sort="Zhu, Chunni" uniqKey="Zhu C" first="Chunni" last="Zhu">Chunni Zhu</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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