Autophagy in the Central Nervous System and Effects of Chloroquine in Mucopolysaccharidosis Type II Mice
Identifieur interne : 000A33 ( Main/Exploration ); précédent : 000A32; suivant : 000A34Autophagy in the Central Nervous System and Effects of Chloroquine in Mucopolysaccharidosis Type II Mice
Auteurs : Mitsuyo Maeda [Japon] ; Toshiyuki Seto [Japon] ; Chiho Kadono ; Hideto Morimoto ; Sachiho Kida ; Mitsuo Suga [Japon] ; Motohiro Nakamura [Japon] ; Yosky Kataoka [Japon] ; Takashi Hamazaki ; Haruo ShintakuSource :
- International Journal of Molecular Sciences [ 1422-0067 ] ; 2019.
Abstract
Mucopolysaccharidosis type II (MPS II) is a rare lysosomal storage disease (LSD) involving a genetic error in iduronic acid-2-sulfatase (IDS) metabolism that leads to accumulation of glycosaminoglycans within intracellular lysosomes. The primary treatment for MPS II, enzyme replacement therapy, is not effective for central nervous system (CNS) symptoms, such as intellectual disability, because the drugs do not cross the blood–brain barrier. Recently, autophagy has been associated with LSDs. In this study, we examined the morphologic relationship between neuronal damage and autophagy in IDS knockout mice using antibodies against subunit c of mitochondrial adenosine triphosphate (ATP) synthetase and p62. Immunohistological changes suggesting autophagy, such as vacuolation, were observed in neurons, microglia, and pericytes throughout the CNS, and the numbers increased over postnatal development. Oral administration of chloroquine, which inhibits autophagy, did not suppress damage to microglia and pericytes, but greatly reduced neuronal vacuolation and eliminated neuronal cells with abnormal inclusions. Thus, decreasing autophagy appears to prevent neuronal degeneration. These results suggest that an autophagy modulator could be used in addition to conventional enzyme replacement therapy to preserve the CNS in patients with MPS II.
Url:
DOI: 10.3390/ijms20235829
PubMed: 31757021
PubMed Central: 6928680
Affiliations:
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Microstructure Analysis Unit, RIKEN-JEOL Collaboration Center, Hyogo 650-0047, Japan;<email>msuga@jeol.co.jp</email> (M.S.);<email>monakamu@jeol.co.jp</email> (M.N.);<email>kataokay@riken.jp</email> (Y.K.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-ijms-20-05829">Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, Hyogo 650-0047, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, Hyogo 650-0047</wicri:regionArea><wicri:noRegion>Hyogo 650-0047</wicri:noRegion></affiliation></author><author><name sortKey="Seto, Toshiyuki" sort="Seto, Toshiyuki" uniqKey="Seto T" first="Toshiyuki" last="Seto">Toshiyuki Seto</name><affiliation wicri:level="1"><nlm:aff id="af3-ijms-20-05829">Department of Medical Genetics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Medical Genetics, Osaka City University Graduate School of Medicine, Osaka 545-8585</wicri:regionArea><wicri:noRegion>Osaka 545-8585</wicri:noRegion></affiliation><affiliation><nlm:aff id="af4-ijms-20-05829">Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan;<email>kadono@med.osaka-cu.ac.jp</email> (C.K.);<email>hammer@med.osaka-cu.ac.jp</email> (T.H.);<email>shintakuh@med.osaka-cu.ac.jp</email> (H.S.)</nlm:aff></affiliation></author><author><name sortKey="Kadono, Chiho" sort="Kadono, Chiho" uniqKey="Kadono C" first="Chiho" last="Kadono">Chiho Kadono</name><affiliation><nlm:aff id="af4-ijms-20-05829">Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan;<email>kadono@med.osaka-cu.ac.jp</email> (C.K.);<email>hammer@med.osaka-cu.ac.jp</email> (T.H.);<email>shintakuh@med.osaka-cu.ac.jp</email> (H.S.)</nlm:aff></affiliation></author><author><name sortKey="Morimoto, Hideto" sort="Morimoto, Hideto" uniqKey="Morimoto H" first="Hideto" last="Morimoto">Hideto Morimoto</name><affiliation><nlm:aff id="af5-ijms-20-05829">JCR Pharmaceuticals Co., Ltd., Hyogo 659-0021, Japan;<email>morimoto-h@jcrpharm.co.jp</email> (H.M.);<email>kida-s@jcrpharm.co.jp</email> (S.K.)</nlm:aff></affiliation></author><author><name sortKey="Kida, Sachiho" sort="Kida, Sachiho" uniqKey="Kida S" first="Sachiho" last="Kida">Sachiho Kida</name><affiliation><nlm:aff id="af5-ijms-20-05829">JCR Pharmaceuticals Co., Ltd., Hyogo 659-0021, Japan;<email>morimoto-h@jcrpharm.co.jp</email> (H.M.);<email>kida-s@jcrpharm.co.jp</email> (S.K.)</nlm:aff></affiliation></author><author><name sortKey="Suga, Mitsuo" sort="Suga, Mitsuo" uniqKey="Suga M" first="Mitsuo" last="Suga">Mitsuo Suga</name><affiliation><nlm:aff id="af1-ijms-20-05829">Multi-Modal Microstructure Analysis Unit, RIKEN-JEOL Collaboration Center, Hyogo 650-0047, Japan;<email>msuga@jeol.co.jp</email> (M.S.);<email>monakamu@jeol.co.jp</email> (M.N.);<email>kataokay@riken.jp</email> (Y.K.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af6-ijms-20-05829">Japan Electron Optics Laboratory (JEOL) Ltd., Tokyo 196-8558, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Japan Electron Optics Laboratory (JEOL) Ltd., Tokyo 196-8558</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Nakamura, Motohiro" sort="Nakamura, Motohiro" uniqKey="Nakamura M" first="Motohiro" last="Nakamura">Motohiro Nakamura</name><affiliation><nlm:aff id="af1-ijms-20-05829">Multi-Modal Microstructure Analysis Unit, RIKEN-JEOL Collaboration Center, Hyogo 650-0047, Japan;<email>msuga@jeol.co.jp</email> (M.S.);<email>monakamu@jeol.co.jp</email> (M.N.);<email>kataokay@riken.jp</email> (Y.K.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af6-ijms-20-05829">Japan Electron Optics Laboratory (JEOL) Ltd., Tokyo 196-8558, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Japan Electron Optics Laboratory (JEOL) Ltd., Tokyo 196-8558</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Kataoka, Yosky" sort="Kataoka, Yosky" uniqKey="Kataoka Y" first="Yosky" last="Kataoka">Yosky Kataoka</name><affiliation><nlm:aff id="af1-ijms-20-05829">Multi-Modal Microstructure Analysis Unit, RIKEN-JEOL Collaboration Center, Hyogo 650-0047, Japan;<email>msuga@jeol.co.jp</email> (M.S.);<email>monakamu@jeol.co.jp</email> (M.N.);<email>kataokay@riken.jp</email> (Y.K.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-ijms-20-05829">Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, Hyogo 650-0047, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory for Cellular Function Imaging, RIKEN Center for Biosystems Dynamics Research, Hyogo 650-0047</wicri:regionArea><wicri:noRegion>Hyogo 650-0047</wicri:noRegion></affiliation></author><author><name sortKey="Hamazaki, Takashi" sort="Hamazaki, Takashi" uniqKey="Hamazaki T" first="Takashi" last="Hamazaki">Takashi Hamazaki</name><affiliation><nlm:aff id="af4-ijms-20-05829">Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan;<email>kadono@med.osaka-cu.ac.jp</email> (C.K.);<email>hammer@med.osaka-cu.ac.jp</email> (T.H.);<email>shintakuh@med.osaka-cu.ac.jp</email> (H.S.)</nlm:aff></affiliation></author><author><name sortKey="Shintaku, Haruo" sort="Shintaku, Haruo" uniqKey="Shintaku H" first="Haruo" last="Shintaku">Haruo Shintaku</name><affiliation><nlm:aff id="af4-ijms-20-05829">Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan;<email>kadono@med.osaka-cu.ac.jp</email> (C.K.);<email>hammer@med.osaka-cu.ac.jp</email> (T.H.);<email>shintakuh@med.osaka-cu.ac.jp</email> (H.S.)</nlm:aff></affiliation></author></analytic><series><title level="j">International Journal of Molecular Sciences</title><idno type="eISSN">1422-0067</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>Mucopolysaccharidosis type II (MPS II) is a rare lysosomal storage disease (LSD) involving a genetic error in iduronic acid-2-sulfatase (IDS) metabolism that leads to accumulation of glycosaminoglycans within intracellular lysosomes. The primary treatment for MPS II, enzyme replacement therapy, is not effective for central nervous system (CNS) symptoms, such as intellectual disability, because the drugs do not cross the blood–brain barrier. Recently, autophagy has been associated with LSDs. In this study, we examined the morphologic relationship between neuronal damage and autophagy in IDS knockout mice using antibodies against subunit c of mitochondrial adenosine triphosphate (ATP) synthetase and p62. Immunohistological changes suggesting autophagy, such as vacuolation, were observed in neurons, microglia, and pericytes throughout the CNS, and the numbers increased over postnatal development. Oral administration of chloroquine, which inhibits autophagy, did not suppress damage to microglia and pericytes, but greatly reduced neuronal vacuolation and eliminated neuronal cells with abnormal inclusions. Thus, decreasing autophagy appears to prevent neuronal degeneration. These results suggest that an autophagy modulator could be used in addition to conventional enzyme replacement therapy to preserve the CNS in patients with MPS II.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Parini, R" uniqKey="Parini R">R. Parini</name></author><author><name sortKey="Deodato, F" uniqKey="Deodato F">F. Deodato</name></author><author><name sortKey="Di Rocco, M" uniqKey="Di Rocco M">M. Di Rocco</name></author><author><name sortKey="Lanino, E" uniqKey="Lanino E">E. Lanino</name></author><author><name sortKey="Locatelli, F" uniqKey="Locatelli F">F. Locatelli</name></author><author><name sortKey="Messina, C" uniqKey="Messina C">C. Messina</name></author><author><name sortKey="Rovelli, A" uniqKey="Rovelli A">A. Rovelli</name></author><author><name sortKey="Scarpa, M" uniqKey="Scarpa M">M. Scarpa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Scarpa, M" uniqKey="Scarpa M">M. 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Freitas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Valayannopoulos, V" uniqKey="Valayannopoulos V">V. Valayannopoulos</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hoshina, H" uniqKey="Hoshina H">H. Hoshina</name></author><author><name sortKey="Shimada, Y" uniqKey="Shimada Y">Y. Shimada</name></author><author><name sortKey="Higuchi, T" uniqKey="Higuchi T">T. Higuchi</name></author><author><name sortKey="Kobayashi, H" uniqKey="Kobayashi H">H. Kobayashi</name></author><author><name sortKey="Ida, H" uniqKey="Ida H">H. Ida</name></author><author><name sortKey="Ohashi, T" uniqKey="Ohashi T">T. Ohashi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johnson, S C" uniqKey="Johnson S">S.C. Johnson</name></author><author><name sortKey="Yanos, M" uniqKey="Yanos M">M. Yanos</name></author><author><name sortKey="Kayser, E B" uniqKey="Kayser E">E.B. Kayser</name></author><author><name sortKey="Quintana, A" uniqKey="Quintana A">A. Quintana</name></author><author><name sortKey="Sangesland, M" uniqKey="Sangesland M">M. Sangesland</name></author><author><name sortKey="Castanza, A" uniqKey="Castanza A">A. Castanza</name></author><author><name sortKey="Uhde Hui, J" uniqKey="Uhde Hui J">J. Uhde Hui</name></author><author><name sortKey="Wall, V Z" uniqKey="Wall V">V.Z. Wall</name></author><author><name sortKey="Gagnidze, A" uniqKey="Gagnidze A">A. Gagnidze</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nicoletti, F" uniqKey="Nicoletti F">F. Nicoletti</name></author><author><name sortKey="Meroni, P" uniqKey="Meroni P">P. Meroni</name></author><author><name sortKey="Mccubrey, J" uniqKey="Mccubrey J">J. McCubrey</name></author><author><name sortKey="Bendtzen, K" uniqKey="Bendtzen K">K. Bendtzen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Higuchi, T" uniqKey="Higuchi T">T. Higuchi</name></author><author><name sortKey="Shimizu, H" uniqKey="Shimizu H">H. Shimizu</name></author><author><name sortKey="Fukuda, T" uniqKey="Fukuda T">T. Fukuda</name></author><author><name sortKey="Kawagoe, S" uniqKey="Kawagoe S">S. Kawagoe</name></author><author><name sortKey="Matsumoto, J" uniqKey="Matsumoto J">J. Matsumoto</name></author><author><name sortKey="Shimada, Y" uniqKey="Shimada Y">Y. Shimada</name></author><author><name sortKey="Kobayashi, H" uniqKey="Kobayashi H">H. Kobayashi</name></author><author><name sortKey="Ida, H" uniqKey="Ida H">H. Ida</name></author><author><name sortKey="Ohashi, T" uniqKey="Ohashi T">T. Ohashi</name></author><author><name sortKey="Morimoto, H" uniqKey="Morimoto H">H. Morimoto</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Japon</li></country><region><li>Région de Kantō</li></region><settlement><li>Tokyo</li></settlement></list><tree><noCountry><name sortKey="Hamazaki, Takashi" sort="Hamazaki, Takashi" uniqKey="Hamazaki T" first="Takashi" last="Hamazaki">Takashi Hamazaki</name><name sortKey="Kadono, Chiho" sort="Kadono, Chiho" uniqKey="Kadono C" first="Chiho" last="Kadono">Chiho Kadono</name><name sortKey="Kida, Sachiho" sort="Kida, Sachiho" uniqKey="Kida S" first="Sachiho" last="Kida">Sachiho Kida</name><name sortKey="Morimoto, Hideto" sort="Morimoto, Hideto" uniqKey="Morimoto H" first="Hideto" last="Morimoto">Hideto Morimoto</name><name sortKey="Shintaku, Haruo" sort="Shintaku, Haruo" uniqKey="Shintaku H" first="Haruo" last="Shintaku">Haruo Shintaku</name></noCountry><country name="Japon"><noRegion><name sortKey="Maeda, Mitsuyo" sort="Maeda, Mitsuyo" uniqKey="Maeda M" first="Mitsuyo" last="Maeda">Mitsuyo Maeda</name></noRegion><name sortKey="Kataoka, Yosky" sort="Kataoka, Yosky" uniqKey="Kataoka Y" first="Yosky" last="Kataoka">Yosky Kataoka</name><name sortKey="Nakamura, Motohiro" sort="Nakamura, Motohiro" uniqKey="Nakamura M" first="Motohiro" last="Nakamura">Motohiro Nakamura</name><name sortKey="Seto, Toshiyuki" sort="Seto, Toshiyuki" uniqKey="Seto T" first="Toshiyuki" last="Seto">Toshiyuki Seto</name><name sortKey="Suga, Mitsuo" sort="Suga, Mitsuo" uniqKey="Suga M" first="Mitsuo" last="Suga">Mitsuo Suga</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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