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Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system

Identifieur interne : 000669 ( Pmc/Checkpoint ); précédent : 000668; suivant : 000670

Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system

Auteurs : Daisuke Yamada [Japon] ; Kenji Kawabe [Japon] ; Ikue Tosa [Japon] ; Shunpei Tsukamoto [Japon] ; Ryota Nakazato ; Miki Kou ; Koichi Fujikawa ; Saki Nakamura ; Mitsuaki Ono [Japon] ; Toshitaka Oohashi [Japon] ; Mari Kaneko ; Shioi Go ; Eiichi Hinoi ; Yukio Yoneda ; Takeshi Takarada [Japon]

Source :

RBID : PMC:6751179

Abstract

The pathophysiological role of mammalian target of rapamycin complex 1 (mTORC1) in neurodegenerative diseases is established, but possible therapeutic targets responsible for its activation in neurons must be explored. Here we identified solute carrier family 38a member 1 (SNAT1, Slc38a1) as a positive regulator of mTORC1 in neurons. Slc38a1flox/flox and Synapsin I-Cre mice were crossed to generate mutant mice in which Slc38a1 was selectively deleted in neurons. Measurement of 2,3,5-triphenyltetrazolium chloride (TTC) or the MAP2-negative area in a mouse model of middle cerebral artery occlusion (MCAO) revealed that Slc38a1 deficiency decreased infarct size. We found a transient increase in the phosphorylation of p70S6k1 (pp70S6k1) and a suppressive effect of rapamycin on infarct size in MCAO mice. Autophagy inhibitors completely mitigated the suppressive effect of SNAT1 deficiency on neuronal cell death under in vitro stroke culture conditions. These results demonstrate that SNAT1 promoted ischemic brain damage via mTOR-autophagy system.


Url:
DOI: 10.1038/s42003-019-0582-4
PubMed: 31552299
PubMed Central: 6751179


Affiliations:


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PMC:6751179

Le document en format XML

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<title xml:lang="en" level="a" type="main">Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system</title>
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<name sortKey="Kawabe, Kenji" sort="Kawabe, Kenji" uniqKey="Kawabe K" first="Kenji" last="Kawabe">Kenji Kawabe</name>
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<name sortKey="Oohashi, Toshitaka" sort="Oohashi, Toshitaka" uniqKey="Oohashi T" first="Toshitaka" last="Oohashi">Toshitaka Oohashi</name>
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<name sortKey="Kaneko, Mari" sort="Kaneko, Mari" uniqKey="Kaneko M" first="Mari" last="Kaneko">Mari Kaneko</name>
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2-2-3 Minatojima Minami, Chuou-ku, Kobe, Hyogo 650-0047 Japan</nlm:aff>
<wicri:noCountry code="subfield">Hyogo 650-0047 Japan</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Go, Shioi" sort="Go, Shioi" uniqKey="Go S" first="Shioi" last="Go">Shioi Go</name>
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<wicri:noCountry code="subfield">Hyogo 650-0047 Japan</wicri:noCountry>
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<name sortKey="Hinoi, Eiichi" sort="Hinoi, Eiichi" uniqKey="Hinoi E" first="Eiichi" last="Hinoi">Eiichi Hinoi</name>
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</author>
<author>
<name sortKey="Yoneda, Yukio" sort="Yoneda, Yukio" uniqKey="Yoneda Y" first="Yukio" last="Yoneda">Yukio Yoneda</name>
<affiliation>
<nlm:aff id="Aff2">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2308 3329</institution-id>
<institution-id institution-id-type="GRID">grid.9707.9</institution-id>
<institution>Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences,</institution>
<institution>Kanazawa University Graduate School,</institution>
</institution-wrap>
Kanazawa, Ishikawa 920-1192 Japan</nlm:aff>
<wicri:noCountry code="subfield">Ishikawa 920-1192 Japan</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Takarada, Takeshi" sort="Takarada, Takeshi" uniqKey="Takarada T" first="Takeshi" last="Takarada">Takeshi Takarada</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 1302 4472</institution-id>
<institution-id institution-id-type="GRID">grid.261356.5</institution-id>
<institution>Department of Regenerative Science,</institution>
<institution>Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,</institution>
</institution-wrap>
Okayama, 700-8558 Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Okayama</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Communications Biology</title>
<idno type="eISSN">2399-3642</idno>
<imprint>
<date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p id="Par1">The pathophysiological role of mammalian target of rapamycin complex 1 (mTORC1) in neurodegenerative diseases is established, but possible therapeutic targets responsible for its activation in neurons must be explored. Here we identified solute carrier family 38a member 1 (SNAT1,
<italic>Slc38a1</italic>
) as a positive regulator of mTORC1 in neurons.
<italic>Slc38a1</italic>
<sup>
<italic>flox/flox</italic>
</sup>
and
<italic>Synapsin I-Cre</italic>
mice were crossed to generate mutant mice in which
<italic>Slc38a1</italic>
was selectively deleted in neurons. Measurement of 2,3,5-triphenyltetrazolium chloride (TTC) or the MAP2-negative area in a mouse model of middle cerebral artery occlusion (MCAO) revealed that
<italic>Slc38a1</italic>
deficiency decreased infarct size. We found a transient increase in the phosphorylation of p70S6k1 (pp70S6k1) and a suppressive effect of rapamycin on infarct size in MCAO mice. Autophagy inhibitors completely mitigated the suppressive effect of SNAT1 deficiency on neuronal cell death under in vitro stroke culture conditions. These results demonstrate that SNAT1 promoted ischemic brain damage via mTOR-autophagy system.</p>
</div>
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</div1>
</back>
</TEI>
<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">Commun Biol</journal-id>
<journal-id journal-id-type="iso-abbrev">Commun Biol</journal-id>
<journal-title-group>
<journal-title>Communications Biology</journal-title>
</journal-title-group>
<issn pub-type="epub">2399-3642</issn>
<publisher>
<publisher-name>Nature Publishing Group UK</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">31552299</article-id>
<article-id pub-id-type="pmc">6751179</article-id>
<article-id pub-id-type="publisher-id">582</article-id>
<article-id pub-id-type="doi">10.1038/s42003-019-0582-4</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Article</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Yamada</surname>
<given-names>Daisuke</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kawabe</surname>
<given-names>Kenji</given-names>
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<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Tosa</surname>
<given-names>Ikue</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Tsukamoto</surname>
<given-names>Shunpei</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Nakazato</surname>
<given-names>Ryota</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kou</surname>
<given-names>Miki</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Fujikawa</surname>
<given-names>Koichi</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Nakamura</surname>
<given-names>Saki</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ono</surname>
<given-names>Mitsuaki</given-names>
</name>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Oohashi</surname>
<given-names>Toshitaka</given-names>
</name>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kaneko</surname>
<given-names>Mari</given-names>
</name>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Go</surname>
<given-names>Shioi</given-names>
</name>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hinoi</surname>
<given-names>Eiichi</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-4624-177X</contrib-id>
<name>
<surname>Yoneda</surname>
<given-names>Yukio</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Takarada</surname>
<given-names>Takeshi</given-names>
</name>
<address>
<email>takarada@okayama-u.ac.jp</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<aff id="Aff1">
<label>1</label>
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 1302 4472</institution-id>
<institution-id institution-id-type="GRID">grid.261356.5</institution-id>
<institution>Department of Regenerative Science,</institution>
<institution>Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,</institution>
</institution-wrap>
Okayama, 700-8558 Japan</aff>
<aff id="Aff2">
<label>2</label>
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2308 3329</institution-id>
<institution-id institution-id-type="GRID">grid.9707.9</institution-id>
<institution>Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences,</institution>
<institution>Kanazawa University Graduate School,</institution>
</institution-wrap>
Kanazawa, Ishikawa 920-1192 Japan</aff>
<aff id="Aff3">
<label>3</label>
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 1302 4472</institution-id>
<institution-id institution-id-type="GRID">grid.261356.5</institution-id>
<institution>Department of Molecular Biology and Biochemistry,</institution>
<institution>Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,</institution>
</institution-wrap>
Okayama, 700-8558 Japan</aff>
<aff id="Aff4">
<label>4</label>
<institution-wrap>
<institution-id institution-id-type="ISNI">0000000094465255</institution-id>
<institution-id institution-id-type="GRID">grid.7597.c</institution-id>
<institution>Laboratory for Animal Resource Development Unit and Genetic Engineering Team,</institution>
<institution>RIKEN Center for Life Science Technologies,</institution>
</institution-wrap>
2-2-3 Minatojima Minami, Chuou-ku, Kobe, Hyogo 650-0047 Japan</aff>
</contrib-group>
<pub-date pub-type="epub">
<day>18</day>
<month>9</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release">
<day>18</day>
<month>9</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection">
<year>2019</year>
</pub-date>
<volume>2</volume>
<elocation-id>346</elocation-id>
<history>
<date date-type="received">
<day>29</day>
<month>8</month>
<year>2018</year>
</date>
<date date-type="accepted">
<day>19</day>
<month>8</month>
<year>2019</year>
</date>
</history>
<permissions>
<copyright-statement>© The Author(s) 2019</copyright-statement>
<license license-type="OpenAccess">
<license-p>
<bold>Open Access</bold>
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
.</license-p>
</license>
</permissions>
<abstract id="Abs1">
<p id="Par1">The pathophysiological role of mammalian target of rapamycin complex 1 (mTORC1) in neurodegenerative diseases is established, but possible therapeutic targets responsible for its activation in neurons must be explored. Here we identified solute carrier family 38a member 1 (SNAT1,
<italic>Slc38a1</italic>
) as a positive regulator of mTORC1 in neurons.
<italic>Slc38a1</italic>
<sup>
<italic>flox/flox</italic>
</sup>
and
<italic>Synapsin I-Cre</italic>
mice were crossed to generate mutant mice in which
<italic>Slc38a1</italic>
was selectively deleted in neurons. Measurement of 2,3,5-triphenyltetrazolium chloride (TTC) or the MAP2-negative area in a mouse model of middle cerebral artery occlusion (MCAO) revealed that
<italic>Slc38a1</italic>
deficiency decreased infarct size. We found a transient increase in the phosphorylation of p70S6k1 (pp70S6k1) and a suppressive effect of rapamycin on infarct size in MCAO mice. Autophagy inhibitors completely mitigated the suppressive effect of SNAT1 deficiency on neuronal cell death under in vitro stroke culture conditions. These results demonstrate that SNAT1 promoted ischemic brain damage via mTOR-autophagy system.</p>
</abstract>
<abstract id="Abs2" abstract-type="web-summary">
<p id="Par2">Yamada et al. demonstrate that solute carrier family 38a member 1 (SNAT1, Slc38a1) is as a positive regulator of mTORC1 that promotes neuronal cell death, using neuron-specific
<italic>Slc38a1</italic>
knockout mice. This study shows that SNAT1 exacerbates ischemic brain damage through mTOR-mediated suppression of autophagy.</p>
</abstract>
<kwd-group kwd-group-type="npg-subject">
<title>Subject terms</title>
<kwd>Cell death in the nervous system</kwd>
<kwd>Neurodegeneration</kwd>
</kwd-group>
<funding-group>
<award-group>
<funding-source>
<institution-wrap>
<institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100001700</institution-id>
<institution>Ministry of Education, Culture, Sports, Science and Technology (MEXT)</institution>
</institution-wrap>
</funding-source>
<award-id>26117507</award-id>
<award-id>16H01332</award-id>
<principal-award-recipient>
<name>
<surname>Takarada</surname>
<given-names>Takeshi</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<custom-meta-group>
<custom-meta>
<meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2018</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
<affiliations>
<list>
<country>
<li>Japon</li>
</country>
</list>
<tree>
<noCountry>
<name sortKey="Fujikawa, Koichi" sort="Fujikawa, Koichi" uniqKey="Fujikawa K" first="Koichi" last="Fujikawa">Koichi Fujikawa</name>
<name sortKey="Go, Shioi" sort="Go, Shioi" uniqKey="Go S" first="Shioi" last="Go">Shioi Go</name>
<name sortKey="Hinoi, Eiichi" sort="Hinoi, Eiichi" uniqKey="Hinoi E" first="Eiichi" last="Hinoi">Eiichi Hinoi</name>
<name sortKey="Kaneko, Mari" sort="Kaneko, Mari" uniqKey="Kaneko M" first="Mari" last="Kaneko">Mari Kaneko</name>
<name sortKey="Kou, Miki" sort="Kou, Miki" uniqKey="Kou M" first="Miki" last="Kou">Miki Kou</name>
<name sortKey="Nakamura, Saki" sort="Nakamura, Saki" uniqKey="Nakamura S" first="Saki" last="Nakamura">Saki Nakamura</name>
<name sortKey="Nakazato, Ryota" sort="Nakazato, Ryota" uniqKey="Nakazato R" first="Ryota" last="Nakazato">Ryota Nakazato</name>
<name sortKey="Yoneda, Yukio" sort="Yoneda, Yukio" uniqKey="Yoneda Y" first="Yukio" last="Yoneda">Yukio Yoneda</name>
</noCountry>
<country name="Japon">
<noRegion>
<name sortKey="Yamada, Daisuke" sort="Yamada, Daisuke" uniqKey="Yamada D" first="Daisuke" last="Yamada">Daisuke Yamada</name>
</noRegion>
<name sortKey="Kawabe, Kenji" sort="Kawabe, Kenji" uniqKey="Kawabe K" first="Kenji" last="Kawabe">Kenji Kawabe</name>
<name sortKey="Ono, Mitsuaki" sort="Ono, Mitsuaki" uniqKey="Ono M" first="Mitsuaki" last="Ono">Mitsuaki Ono</name>
<name sortKey="Oohashi, Toshitaka" sort="Oohashi, Toshitaka" uniqKey="Oohashi T" first="Toshitaka" last="Oohashi">Toshitaka Oohashi</name>
<name sortKey="Takarada, Takeshi" sort="Takarada, Takeshi" uniqKey="Takarada T" first="Takeshi" last="Takarada">Takeshi Takarada</name>
<name sortKey="Tosa, Ikue" sort="Tosa, Ikue" uniqKey="Tosa I" first="Ikue" last="Tosa">Ikue Tosa</name>
<name sortKey="Tsukamoto, Shunpei" sort="Tsukamoto, Shunpei" uniqKey="Tsukamoto S" first="Shunpei" last="Tsukamoto">Shunpei Tsukamoto</name>
</country>
</tree>
</affiliations>
</record>

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