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Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo
Mitochondrial dysfunction is heavily implicated in Parkinson disease (PD) as exemplified by the finding of an increased frequency of respiratory chain-deficient dopamine (DA) neurons in affected patients. An inherited form of PD is caused by impaired function of Parkin, an E3 ubiquitin ligase report...
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Published in: | Proceedings of the National Academy of Sciences - PNAS 2011-08, Vol.108 (31), p.12937-12942 |
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creator | Sterky, Fredrik H Lee, Seungmin Wibom, Rolf Olson, Lars Larsson, Nils-Göran |
description | Mitochondrial dysfunction is heavily implicated in Parkinson disease (PD) as exemplified by the finding of an increased frequency of respiratory chain-deficient dopamine (DA) neurons in affected patients. An inherited form of PD is caused by impaired function of Parkin, an E3 ubiquitin ligase reported to translocate to defective mitochondria in vitro to facilitate their clearance. We have developed a reporter mouse to assess mitochondrial morphology in DA neurons in vivo and show here that respiratory chain deficiency leads to fragmentation of the mitochondrial network and to the formation of large cytoplasmic bodies derived from mitochondria. Surprisingly, the dysfunctional mitochondria do not recruit Parkin in vivo, and neither the clearance of defective mitochondria nor the neurodegeneration phenotype is affected by the absence of Parkin. We also show that anterograde axonal transport of mitochondria is impaired in respiratory chain-deficient DA neurons, leading to a decreased supply of mitochondria to the axonal terminals. |
doi_str_mv | 10.1073/pnas.1103295108 |
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An inherited form of PD is caused by impaired function of Parkin, an E3 ubiquitin ligase reported to translocate to defective mitochondria in vitro to facilitate their clearance. We have developed a reporter mouse to assess mitochondrial morphology in DA neurons in vivo and show here that respiratory chain deficiency leads to fragmentation of the mitochondrial network and to the formation of large cytoplasmic bodies derived from mitochondria. Surprisingly, the dysfunctional mitochondria do not recruit Parkin in vivo, and neither the clearance of defective mitochondria nor the neurodegeneration phenotype is affected by the absence of Parkin. We also show that anterograde axonal transport of mitochondria is impaired in respiratory chain-deficient DA neurons, leading to a decreased supply of mitochondria to the axonal terminals.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1103295108</identifier><identifier>PMID: 21768369</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Axonal transport ; Axons ; Axons - metabolism ; Biological Sciences ; Blotting, Western ; Brain ; Cell aggregates ; Dopamine ; Dopamine - metabolism ; Electron transport ; electron transport chain ; Enzymes ; Female ; Genetic mutation ; HeLa Cells ; Humans ; Immunohistochemistry ; Luminescent Proteins - genetics ; Luminescent Proteins - metabolism ; Male ; Medicin och hälsovetenskap ; Membrane potential ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Microscopy, Fluorescence ; Mitochondria ; Mitochondria - genetics ; Mitochondria - metabolism ; Mitochondrial Diseases - genetics ; Mitochondrial Diseases - metabolism ; Mitochondrial Diseases - pathology ; Mitochondrial DNA ; Movement disorders ; Neurodegeneration ; Neurodegenerative diseases ; Neurons ; Neurons - metabolism ; Neurons - pathology ; Parkin protein ; Parkinson disease ; Parkinson's disease ; patients ; phenotype ; Protein Transport ; Recruitment ; Respiration ; respiratory rate ; Ubiquitin-protein ligase ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2011-08, Vol.108 (31), p.12937-12942</ispartof><rights>copyright © 1993–2008 by the National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Aug 2, 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c677t-d8084b5eb59237294fd9165850a82b7d8d55589c040f67c6d69ceee956df97de3</citedby><cites>FETCH-LOGICAL-c677t-d8084b5eb59237294fd9165850a82b7d8d55589c040f67c6d69ceee956df97de3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/108/31.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/27979115$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/27979115$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793,58238,58471</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21768369$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:123024396$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Sterky, Fredrik H</creatorcontrib><creatorcontrib>Lee, Seungmin</creatorcontrib><creatorcontrib>Wibom, Rolf</creatorcontrib><creatorcontrib>Olson, Lars</creatorcontrib><creatorcontrib>Larsson, Nils-Göran</creatorcontrib><title>Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Mitochondrial dysfunction is heavily implicated in Parkinson disease (PD) as exemplified by the finding of an increased frequency of respiratory chain-deficient dopamine (DA) neurons in affected patients. An inherited form of PD is caused by impaired function of Parkin, an E3 ubiquitin ligase reported to translocate to defective mitochondria in vitro to facilitate their clearance. We have developed a reporter mouse to assess mitochondrial morphology in DA neurons in vivo and show here that respiratory chain deficiency leads to fragmentation of the mitochondrial network and to the formation of large cytoplasmic bodies derived from mitochondria. Surprisingly, the dysfunctional mitochondria do not recruit Parkin in vivo, and neither the clearance of defective mitochondria nor the neurodegeneration phenotype is affected by the absence of Parkin. We also show that anterograde axonal transport of mitochondria is impaired in respiratory chain-deficient DA neurons, leading to a decreased supply of mitochondria to the axonal terminals.</description><subject>Animals</subject><subject>Axonal transport</subject><subject>Axons</subject><subject>Axons - metabolism</subject><subject>Biological Sciences</subject><subject>Blotting, Western</subject><subject>Brain</subject><subject>Cell aggregates</subject><subject>Dopamine</subject><subject>Dopamine - metabolism</subject><subject>Electron transport</subject><subject>electron transport chain</subject><subject>Enzymes</subject><subject>Female</subject><subject>Genetic mutation</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Luminescent Proteins - genetics</subject><subject>Luminescent Proteins - metabolism</subject><subject>Male</subject><subject>Medicin och hälsovetenskap</subject><subject>Membrane potential</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Microscopy, Fluorescence</subject><subject>Mitochondria</subject><subject>Mitochondria - genetics</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondrial Diseases - genetics</subject><subject>Mitochondrial Diseases - metabolism</subject><subject>Mitochondrial Diseases - pathology</subject><subject>Mitochondrial DNA</subject><subject>Movement disorders</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Neurons</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Parkin protein</subject><subject>Parkinson disease</subject><subject>Parkinson's disease</subject><subject>patients</subject><subject>phenotype</subject><subject>Protein Transport</subject><subject>Recruitment</subject><subject>Respiration</subject><subject>respiratory rate</subject><subject>Ubiquitin-protein ligase</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNp9kktv1DAUhSMEokNhzQqw2MAmrR_xa4OEKh6VKoEEXVue-GbG04md2plBlfjxOMy0Q5Fgk9f9zonvvaeqnhN8QrBkp0Ow-YQQzKjmBKsH1YxgTWrRaPywmmFMZa0a2hxVT3JeYYw1V_hxdUSJFIoJPat-nveD9Qkc6v0Y22UMLnm7RmOyIQ8xjcgGh77adOVD7YODAcoljMjBAgIkO_oYUOxQgjz48hrTDWqXttAOOt_632wcbO8DoACbFENGPqCt38an1aPOrjM829-Pq8uPH76ffa4vvnw6P3t_UbdCyrF2CqtmzmHONWWS6qZzmgiuOLaKzqVTjnOudIsb3AnZCid0CwCaC9dp6YAdV_XON_-AYTM3Q_K9TTcmWm_2n67KExjeMEx04fU_-SFFdxDdCgllmDZMi6J9t9MWoAfXlv6TXd-3uFcJfmkWcWsY4VjT6edv9gYpXm8gj6b3uYX12gaIm2yUKouWZbWFfPtfskSBNVQoOZ3q9V_oKm5SKEOf_MpIG6YKdLqD2hRzTtDdnZpgM8XNTHEzh7gVxcs_m73jb_NVALQHJuXBTpV2y9A0kwV5sUNWuYTnYCG11ITwUn-1q3c2GrtIPpvLbxQTgcuqaKMk-wXegvKu</recordid><startdate>20110802</startdate><enddate>20110802</enddate><creator>Sterky, Fredrik H</creator><creator>Lee, Seungmin</creator><creator>Wibom, Rolf</creator><creator>Olson, Lars</creator><creator>Larsson, Nils-Göran</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><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><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20110802</creationdate><title>Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo</title><author>Sterky, Fredrik H ; Lee, Seungmin ; Wibom, Rolf ; Olson, Lars ; Larsson, Nils-Göran</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c677t-d8084b5eb59237294fd9165850a82b7d8d55589c040f67c6d69ceee956df97de3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Axonal transport</topic><topic>Axons</topic><topic>Axons - metabolism</topic><topic>Biological Sciences</topic><topic>Blotting, Western</topic><topic>Brain</topic><topic>Cell aggregates</topic><topic>Dopamine</topic><topic>Dopamine - metabolism</topic><topic>Electron transport</topic><topic>electron transport chain</topic><topic>Enzymes</topic><topic>Female</topic><topic>Genetic mutation</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Luminescent Proteins - genetics</topic><topic>Luminescent Proteins - metabolism</topic><topic>Male</topic><topic>Medicin och hälsovetenskap</topic><topic>Membrane potential</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Microscopy, Fluorescence</topic><topic>Mitochondria</topic><topic>Mitochondria - genetics</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondrial Diseases - genetics</topic><topic>Mitochondrial Diseases - metabolism</topic><topic>Mitochondrial Diseases - pathology</topic><topic>Mitochondrial DNA</topic><topic>Movement disorders</topic><topic>Neurodegeneration</topic><topic>Neurodegenerative diseases</topic><topic>Neurons</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>Parkin protein</topic><topic>Parkinson disease</topic><topic>Parkinson's disease</topic><topic>patients</topic><topic>phenotype</topic><topic>Protein Transport</topic><topic>Recruitment</topic><topic>Respiration</topic><topic>respiratory rate</topic><topic>Ubiquitin-protein ligase</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sterky, Fredrik H</creatorcontrib><creatorcontrib>Lee, Seungmin</creatorcontrib><creatorcontrib>Wibom, Rolf</creatorcontrib><creatorcontrib>Olson, Lars</creatorcontrib><creatorcontrib>Larsson, Nils-Göran</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sterky, Fredrik H</au><au>Lee, Seungmin</au><au>Wibom, Rolf</au><au>Olson, Lars</au><au>Larsson, Nils-Göran</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2011-08-02</date><risdate>2011</risdate><volume>108</volume><issue>31</issue><spage>12937</spage><epage>12942</epage><pages>12937-12942</pages><issn>0027-8424</issn><issn>1091-6490</issn><eissn>1091-6490</eissn><abstract>Mitochondrial dysfunction is heavily implicated in Parkinson disease (PD) as exemplified by the finding of an increased frequency of respiratory chain-deficient dopamine (DA) neurons in affected patients. An inherited form of PD is caused by impaired function of Parkin, an E3 ubiquitin ligase reported to translocate to defective mitochondria in vitro to facilitate their clearance. We have developed a reporter mouse to assess mitochondrial morphology in DA neurons in vivo and show here that respiratory chain deficiency leads to fragmentation of the mitochondrial network and to the formation of large cytoplasmic bodies derived from mitochondria. Surprisingly, the dysfunctional mitochondria do not recruit Parkin in vivo, and neither the clearance of defective mitochondria nor the neurodegeneration phenotype is affected by the absence of Parkin. We also show that anterograde axonal transport of mitochondria is impaired in respiratory chain-deficient DA neurons, leading to a decreased supply of mitochondria to the axonal terminals.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21768369</pmid><doi>10.1073/pnas.1103295108</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Axonal transport Axons Axons - metabolism Biological Sciences Blotting, Western Brain Cell aggregates Dopamine Dopamine - metabolism Electron transport electron transport chain Enzymes Female Genetic mutation HeLa Cells Humans Immunohistochemistry Luminescent Proteins - genetics Luminescent Proteins - metabolism Male Medicin och hälsovetenskap Membrane potential Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Microscopy, Fluorescence Mitochondria Mitochondria - genetics Mitochondria - metabolism Mitochondrial Diseases - genetics Mitochondrial Diseases - metabolism Mitochondrial Diseases - pathology Mitochondrial DNA Movement disorders Neurodegeneration Neurodegenerative diseases Neurons Neurons - metabolism Neurons - pathology Parkin protein Parkinson disease Parkinson's disease patients phenotype Protein Transport Recruitment Respiration respiratory rate Ubiquitin-protein ligase Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism |
title | Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo |
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