Parkinson’s disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling
Mutations in the iPLA2-VIA/PLA2G6 gene are responsible for PARK14-linked Parkinson’s disease (PD) with α-synucleinopathy. However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA–deficient Drosophil...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2019-10, Vol.116 (41), p.20689-20699 |
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| creator | Mori, Akio Hatano, Taku Inoshita, Tsuyoshi Shiba-Fukushima, Kahori Koinuma, Takahiro Meng, Hongrui Kubo, Shin-ichiro Spratt, Spencer Cui, Changxu Yamashita, Chikara Miki, Yoshimi Yamamoto, Kei Hirabayashi, Tetsuya Murakami, Makoto Takahashi, Yoshikazu Shindou, Hideo Nonaka, Takashi Hasegawa, Masato Okuzumi, Ayami Imai, Yuzuru Hattori, Nobutaka |
| description | Mutations in the iPLA2-VIA/PLA2G6 gene are responsible for PARK14-linked Parkinson’s disease (PD) with α-synucleinopathy. However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA–deficient Drosophila exhibits defects in neurotransmission during early developmental stages and progressive cell loss throughout the brain, including degeneration of the DA neurons. Lipid analysis of brain tissues reveals that the acyl-chain length of phospholipids is shortened by iPLA2-VIA loss, which causes endoplasmic reticulum (ER) stress through membrane lipid disequilibrium. The introduction of wild-type human iPLA2-VIA or the mitochondria–ER contact site-resident protein C19orf12 in iPLA2-VIA–deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, iPLA2-VIA A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by iPLA2-VIA loss is suppressed by the administration of linoleic acid, correcting the brain lipid composition. Our findings suggest that membrane remodeling by iPLA2-VIA is required for the survival of DA neurons and α-Syn stability. |
| doi_str_mv | 10.1073/pnas.1902958116 |
| format | Article |
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However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA–deficient Drosophila exhibits defects in neurotransmission during early developmental stages and progressive cell loss throughout the brain, including degeneration of the DA neurons. Lipid analysis of brain tissues reveals that the acyl-chain length of phospholipids is shortened by iPLA2-VIA loss, which causes endoplasmic reticulum (ER) stress through membrane lipid disequilibrium. The introduction of wild-type human iPLA2-VIA or the mitochondria–ER contact site-resident protein C19orf12 in iPLA2-VIA–deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, iPLA2-VIA A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by iPLA2-VIA loss is suppressed by the administration of linoleic acid, correcting the brain lipid composition. Our findings suggest that membrane remodeling by iPLA2-VIA is required for the survival of DA neurons and α-Syn stability.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1902958116</identifier><identifier>PMID: 31548400</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Acceleration ; Agglomeration ; alpha-Synuclein - chemistry ; alpha-Synuclein - genetics ; alpha-Synuclein - metabolism ; Animals ; Animals, Genetically Modified ; Biological Sciences ; Brain ; Brain - metabolism ; Brain - pathology ; Cell Membrane - metabolism ; Cell Membrane - pathology ; Composition ; Degeneration ; Developmental stages ; Dopamine receptors ; Dopaminergic Neurons - metabolism ; Dopaminergic Neurons - pathology ; Drosophila melanogaster ; Drosophila Proteins - genetics ; Drosophila Proteins - metabolism ; Endoplasmic reticulum ; Endoplasmic Reticulum Stress ; Female ; Fruit flies ; Group VI Phospholipases A2 - genetics ; Group VI Phospholipases A2 - metabolism ; Group X Phospholipases A2 - genetics ; Group X Phospholipases A2 - metabolism ; Humans ; Linoleic acid ; Lipid composition ; Lipids ; Male ; Membranes ; Missense mutant ; Mitochondria ; Mitochondria - metabolism ; Mitochondria - pathology ; Mitochondrial Proteins - genetics ; Mitochondrial Proteins - metabolism ; Movement disorders ; Mutation ; Nerve Degeneration - metabolism ; Nerve Degeneration - pathology ; Neurodegeneration ; Neurodegenerative diseases ; Neurons ; Neurotransmission ; Parkinson Disease - metabolism ; Parkinson Disease - pathology ; Parkinson's disease ; Phenotypes ; Phospholipase A2 ; Phospholipids ; Phospholipids - metabolism ; PNAS Plus ; Stability ; Synaptic Transmission ; Synuclein</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2019-10, Vol.116 (41), p.20689-20699</ispartof><rights>Copyright © 2019 the Author(s). Published by PNAS.</rights><rights>Copyright National Academy of Sciences Oct 8, 2019</rights><rights>Copyright © 2019 the Author(s). Published by PNAS. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c575t-375bb82e0d2bcf385fcfa943466a30a9d7251acc30e55a2d99d1ba5a019f2ba33</citedby><cites>FETCH-LOGICAL-c575t-375bb82e0d2bcf385fcfa943466a30a9d7251acc30e55a2d99d1ba5a019f2ba33</cites><orcidid>0000-0001-8099-5367 ; 0000-0002-0830-9403 ; 0000-0002-6808-0444 ; 0000-0002-8587-0333 ; 0000-0003-2924-5231</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26858021$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26858021$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31548400$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mori, Akio</creatorcontrib><creatorcontrib>Hatano, Taku</creatorcontrib><creatorcontrib>Inoshita, Tsuyoshi</creatorcontrib><creatorcontrib>Shiba-Fukushima, Kahori</creatorcontrib><creatorcontrib>Koinuma, Takahiro</creatorcontrib><creatorcontrib>Meng, Hongrui</creatorcontrib><creatorcontrib>Kubo, Shin-ichiro</creatorcontrib><creatorcontrib>Spratt, Spencer</creatorcontrib><creatorcontrib>Cui, Changxu</creatorcontrib><creatorcontrib>Yamashita, Chikara</creatorcontrib><creatorcontrib>Miki, Yoshimi</creatorcontrib><creatorcontrib>Yamamoto, Kei</creatorcontrib><creatorcontrib>Hirabayashi, Tetsuya</creatorcontrib><creatorcontrib>Murakami, Makoto</creatorcontrib><creatorcontrib>Takahashi, Yoshikazu</creatorcontrib><creatorcontrib>Shindou, Hideo</creatorcontrib><creatorcontrib>Nonaka, Takashi</creatorcontrib><creatorcontrib>Hasegawa, Masato</creatorcontrib><creatorcontrib>Okuzumi, Ayami</creatorcontrib><creatorcontrib>Imai, Yuzuru</creatorcontrib><creatorcontrib>Hattori, Nobutaka</creatorcontrib><title>Parkinson’s disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Mutations in the iPLA2-VIA/PLA2G6 gene are responsible for PARK14-linked Parkinson’s disease (PD) with α-synucleinopathy. However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA–deficient Drosophila exhibits defects in neurotransmission during early developmental stages and progressive cell loss throughout the brain, including degeneration of the DA neurons. Lipid analysis of brain tissues reveals that the acyl-chain length of phospholipids is shortened by iPLA2-VIA loss, which causes endoplasmic reticulum (ER) stress through membrane lipid disequilibrium. The introduction of wild-type human iPLA2-VIA or the mitochondria–ER contact site-resident protein C19orf12 in iPLA2-VIA–deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, iPLA2-VIA A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by iPLA2-VIA loss is suppressed by the administration of linoleic acid, correcting the brain lipid composition. Our findings suggest that membrane remodeling by iPLA2-VIA is required for the survival of DA neurons and α-Syn stability.</description><subject>Acceleration</subject><subject>Agglomeration</subject><subject>alpha-Synuclein - chemistry</subject><subject>alpha-Synuclein - genetics</subject><subject>alpha-Synuclein - metabolism</subject><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Biological Sciences</subject><subject>Brain</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Cell Membrane - metabolism</subject><subject>Cell Membrane - pathology</subject><subject>Composition</subject><subject>Degeneration</subject><subject>Developmental stages</subject><subject>Dopamine receptors</subject><subject>Dopaminergic Neurons - metabolism</subject><subject>Dopaminergic Neurons - pathology</subject><subject>Drosophila melanogaster</subject><subject>Drosophila Proteins - genetics</subject><subject>Drosophila Proteins - metabolism</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum Stress</subject><subject>Female</subject><subject>Fruit flies</subject><subject>Group VI Phospholipases A2 - genetics</subject><subject>Group VI Phospholipases A2 - metabolism</subject><subject>Group X Phospholipases A2 - genetics</subject><subject>Group X Phospholipases A2 - metabolism</subject><subject>Humans</subject><subject>Linoleic acid</subject><subject>Lipid composition</subject><subject>Lipids</subject><subject>Male</subject><subject>Membranes</subject><subject>Missense mutant</subject><subject>Mitochondria</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - pathology</subject><subject>Mitochondrial Proteins - genetics</subject><subject>Mitochondrial Proteins - metabolism</subject><subject>Movement disorders</subject><subject>Mutation</subject><subject>Nerve Degeneration - metabolism</subject><subject>Nerve Degeneration - pathology</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Neurons</subject><subject>Neurotransmission</subject><subject>Parkinson Disease - metabolism</subject><subject>Parkinson Disease - pathology</subject><subject>Parkinson's disease</subject><subject>Phenotypes</subject><subject>Phospholipase A2</subject><subject>Phospholipids</subject><subject>Phospholipids - metabolism</subject><subject>PNAS Plus</subject><subject>Stability</subject><subject>Synaptic Transmission</subject><subject>Synuclein</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU2OEzEQhS0EYkJgzQpkiQ2bnvin7W5vkKIRM4wUiVkAW6va7U4cuu1gd4-UHRsOMcfgIhyCk-AoQ_hZVUnvq6eqegg9p-Sckoovdh7SOVWEKVFTKh-gGSWKFrJU5CGaEcKqoi5ZeYaepLQlhGSMPEZnnIqyLgmZoW83ED87n4L_-fUu4dYlC8kWkFIwDkbbYnezWrLi0_VycWiuJI52PfVZStjbKQYPPe4mb0YXfMLgW_zje5H2fjK9dR6nERrXu3GPx00M03qDBzs0EbzNRkNobe_8-il61EGf7LP7OkcfL99-uHhXrN5fXV8sV4URlRgLXommqZklLWtMx2vRmQ5UyUspgRNQbcUEBWM4sUIAa5VqaQMCCFUda4DzOXpz9N1NzWBbY_0Yode76AaIex3A6X8V7zZ6HW61rGql8sPn6PW9QQxfJptGPbhkbN_ne8KUNGNKSinyGhl99R-6DVPM38oUJ7yijJUHw8WRMjGkFG13WoYSfYhYHyLWfyLOEy__vuHE_840Ay-OwDaNIZ50JuscPqP8F3HcsJk</recordid><startdate>20191008</startdate><enddate>20191008</enddate><creator>Mori, Akio</creator><creator>Hatano, Taku</creator><creator>Inoshita, Tsuyoshi</creator><creator>Shiba-Fukushima, Kahori</creator><creator>Koinuma, Takahiro</creator><creator>Meng, Hongrui</creator><creator>Kubo, Shin-ichiro</creator><creator>Spratt, Spencer</creator><creator>Cui, Changxu</creator><creator>Yamashita, Chikara</creator><creator>Miki, Yoshimi</creator><creator>Yamamoto, Kei</creator><creator>Hirabayashi, Tetsuya</creator><creator>Murakami, Makoto</creator><creator>Takahashi, Yoshikazu</creator><creator>Shindou, Hideo</creator><creator>Nonaka, Takashi</creator><creator>Hasegawa, Masato</creator><creator>Okuzumi, Ayami</creator><creator>Imai, Yuzuru</creator><creator>Hattori, Nobutaka</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8099-5367</orcidid><orcidid>https://orcid.org/0000-0002-0830-9403</orcidid><orcidid>https://orcid.org/0000-0002-6808-0444</orcidid><orcidid>https://orcid.org/0000-0002-8587-0333</orcidid><orcidid>https://orcid.org/0000-0003-2924-5231</orcidid></search><sort><creationdate>20191008</creationdate><title>Parkinson’s disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling</title><author>Mori, Akio ; Hatano, Taku ; Inoshita, Tsuyoshi ; Shiba-Fukushima, Kahori ; Koinuma, Takahiro ; Meng, Hongrui ; Kubo, Shin-ichiro ; Spratt, Spencer ; Cui, Changxu ; Yamashita, Chikara ; Miki, Yoshimi ; Yamamoto, Kei ; Hirabayashi, Tetsuya ; Murakami, Makoto ; Takahashi, Yoshikazu ; Shindou, Hideo ; Nonaka, Takashi ; Hasegawa, Masato ; Okuzumi, Ayami ; Imai, Yuzuru ; Hattori, Nobutaka</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c575t-375bb82e0d2bcf385fcfa943466a30a9d7251acc30e55a2d99d1ba5a019f2ba33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acceleration</topic><topic>Agglomeration</topic><topic>alpha-Synuclein - chemistry</topic><topic>alpha-Synuclein - genetics</topic><topic>alpha-Synuclein - metabolism</topic><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Biological Sciences</topic><topic>Brain</topic><topic>Brain - metabolism</topic><topic>Brain - pathology</topic><topic>Cell Membrane - metabolism</topic><topic>Cell Membrane - pathology</topic><topic>Composition</topic><topic>Degeneration</topic><topic>Developmental stages</topic><topic>Dopamine receptors</topic><topic>Dopaminergic Neurons - metabolism</topic><topic>Dopaminergic Neurons - pathology</topic><topic>Drosophila melanogaster</topic><topic>Drosophila Proteins - genetics</topic><topic>Drosophila Proteins - metabolism</topic><topic>Endoplasmic reticulum</topic><topic>Endoplasmic Reticulum Stress</topic><topic>Female</topic><topic>Fruit flies</topic><topic>Group VI Phospholipases A2 - genetics</topic><topic>Group VI Phospholipases A2 - metabolism</topic><topic>Group X Phospholipases A2 - genetics</topic><topic>Group X Phospholipases A2 - 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PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2019-10-08</date><risdate>2019</risdate><volume>116</volume><issue>41</issue><spage>20689</spage><epage>20699</epage><pages>20689-20699</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Mutations in the iPLA2-VIA/PLA2G6 gene are responsible for PARK14-linked Parkinson’s disease (PD) with α-synucleinopathy. However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA–deficient Drosophila exhibits defects in neurotransmission during early developmental stages and progressive cell loss throughout the brain, including degeneration of the DA neurons. Lipid analysis of brain tissues reveals that the acyl-chain length of phospholipids is shortened by iPLA2-VIA loss, which causes endoplasmic reticulum (ER) stress through membrane lipid disequilibrium. The introduction of wild-type human iPLA2-VIA or the mitochondria–ER contact site-resident protein C19orf12 in iPLA2-VIA–deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, iPLA2-VIA A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by iPLA2-VIA loss is suppressed by the administration of linoleic acid, correcting the brain lipid composition. Our findings suggest that membrane remodeling by iPLA2-VIA is required for the survival of DA neurons and α-Syn stability.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>31548400</pmid><doi>10.1073/pnas.1902958116</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-8099-5367</orcidid><orcidid>https://orcid.org/0000-0002-0830-9403</orcidid><orcidid>https://orcid.org/0000-0002-6808-0444</orcidid><orcidid>https://orcid.org/0000-0002-8587-0333</orcidid><orcidid>https://orcid.org/0000-0003-2924-5231</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6789907 |
| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Acceleration Agglomeration alpha-Synuclein - chemistry alpha-Synuclein - genetics alpha-Synuclein - metabolism Animals Animals, Genetically Modified Biological Sciences Brain Brain - metabolism Brain - pathology Cell Membrane - metabolism Cell Membrane - pathology Composition Degeneration Developmental stages Dopamine receptors Dopaminergic Neurons - metabolism Dopaminergic Neurons - pathology Drosophila melanogaster Drosophila Proteins - genetics Drosophila Proteins - metabolism Endoplasmic reticulum Endoplasmic Reticulum Stress Female Fruit flies Group VI Phospholipases A2 - genetics Group VI Phospholipases A2 - metabolism Group X Phospholipases A2 - genetics Group X Phospholipases A2 - metabolism Humans Linoleic acid Lipid composition Lipids Male Membranes Missense mutant Mitochondria Mitochondria - metabolism Mitochondria - pathology Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Movement disorders Mutation Nerve Degeneration - metabolism Nerve Degeneration - pathology Neurodegeneration Neurodegenerative diseases Neurons Neurotransmission Parkinson Disease - metabolism Parkinson Disease - pathology Parkinson's disease Phenotypes Phospholipase A2 Phospholipids Phospholipids - metabolism PNAS Plus Stability Synaptic Transmission Synuclein |
| title | Parkinson’s disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T08%3A57%3A32IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Parkinson%E2%80%99s%20disease-associated%20iPLA2-VIA/PLA2G6%20regulates%20neuronal%20functions%20and%20%CE%B1-synuclein%20stability%20through%20membrane%20remodeling&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Mori,%20Akio&rft.date=2019-10-08&rft.volume=116&rft.issue=41&rft.spage=20689&rft.epage=20699&rft.pages=20689-20699&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.1902958116&rft_dat=%3Cjstor_pubme%3E26858021%3C/jstor_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2303712247&rft_id=info:pmid/31548400&rft_jstor_id=26858021&rfr_iscdi=true |