Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin
Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposur...
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Veröffentlicht in: | Nature 2006-06, Vol.441 (7097), p.1162-1166 |
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description | Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology1. Recently, multiple genes mediating familial forms of Parkinson's disease have been identified, including PTEN-induced kinase 1 (PINK1 ; PARK6 ) and parkin (PARK2 ), which are also associated with sporadic forms of Parkinson's disease. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence. So far, no in vivo studies have been reported for pink1 in any model system. Here we show that removal of Drosophila PINK1 homologue (CG4523; hereafter called pink1) function results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress. Pink1 localizes to mitochondria, and mitochondrial cristae are fragmented in pink1 mutants. Expression of human PINK1 in the Drosophila testes restores male fertility and normal mitochondrial morphology in a portion of pink1 mutants, demonstrating functional conservation between human and Drosophila Pink1. Loss of Drosophila parkin shows phenotypes similar to loss of pink1 function. Notably, overexpression of parkin rescues the male sterility and mitochondrial morphology defects of pink1 mutants, whereas double mutants removing both pink1 and parkin function show muscle phenotypes identical to those observed in either mutant alone. These observations suggest that pink1 and parkin function, at least in part, in the same pathway, with pink1 functioning upstream of parkin. The role of the pink1-parkin pathway in regulating mitochondrial function underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson's disease pathogenesis. |
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Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology1. Recently, multiple genes mediating familial forms of Parkinson's disease have been identified, including PTEN-induced kinase 1 (PINK1 ; PARK6 ) and parkin (PARK2 ), which are also associated with sporadic forms of Parkinson's disease. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence. So far, no in vivo studies have been reported for pink1 in any model system. Here we show that removal of Drosophila PINK1 homologue (CG4523; hereafter called pink1) function results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress. Pink1 localizes to mitochondria, and mitochondrial cristae are fragmented in pink1 mutants. Expression of human PINK1 in the Drosophila testes restores male fertility and normal mitochondrial morphology in a portion of pink1 mutants, demonstrating functional conservation between human and Drosophila Pink1. Loss of Drosophila parkin shows phenotypes similar to loss of pink1 function. Notably, overexpression of parkin rescues the male sterility and mitochondrial morphology defects of pink1 mutants, whereas double mutants removing both pink1 and parkin function show muscle phenotypes identical to those observed in either mutant alone. These observations suggest that pink1 and parkin function, at least in part, in the same pathway, with pink1 functioning upstream of parkin. The role of the pink1-parkin pathway in regulating mitochondrial function underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson's disease pathogenesis.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>EISSN: 1476-4679</identifier><identifier>DOI: 10.1038/nature04779</identifier><identifier>PMID: 16672981</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Adenosine Triphosphate - metabolism ; Animals ; Apoptosis ; cytochemistry ; cytopathogenicity ; Drosophila ; Drosophila melanogaster ; Drosophila melanogaster - cytology ; Drosophila melanogaster - enzymology ; Drosophila melanogaster - genetics ; Drosophila melanogaster - physiology ; Drosophila Proteins - genetics ; Drosophila Proteins - metabolism ; Epistasis, Genetic ; Fertility ; Genetic Complementation Test ; Genetics ; Humanities and Social Sciences ; Humans ; Infertility, Male - genetics ; Infertility, Male - pathology ; Insects ; letter ; Longevity - genetics ; Longevity - physiology ; Male ; male fertility ; Male sterility ; mitochondria ; Mitochondria - pathology ; Mitochondria - physiology ; Mitochondrial DNA ; multidisciplinary ; muscles ; Muscles - metabolism ; Muscles - pathology ; Mutants ; Mutation - genetics ; Neurological disorders ; Neurons ; Oxidative stress ; parkin ; Parkinson Disease - genetics ; Parkinson Disease - pathology ; Parkinson Disease - physiopathology ; Parkinson's disease ; Pathology ; Phenotype ; Protein Kinases - genetics ; Protein Kinases - metabolism ; Protein Transport ; Proteins ; PTEN-induced kinase 1 ; Science ; Science (multidisciplinary) ; spermatids ; Spermatids - metabolism ; Spermatids - pathology ; tissue degeneration ; Toxins ; Ubiquitin-Protein Ligases</subject><ispartof>Nature, 2006-06, Vol.441 (7097), p.1162-1166</ispartof><rights>Springer Nature Limited 2006</rights><rights>COPYRIGHT 2006 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jun 29, 2006</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c668t-e09fa0c25e653fe28ad02b5378eee74d7398e53ce5a001c1ac436bc4ae461a6a3</citedby><cites>FETCH-LOGICAL-c668t-e09fa0c25e653fe28ad02b5378eee74d7398e53ce5a001c1ac436bc4ae461a6a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2727,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16672981$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Clark, I.E</creatorcontrib><creatorcontrib>Dodson, M.W</creatorcontrib><creatorcontrib>Jiang, C</creatorcontrib><creatorcontrib>Cao, J.H</creatorcontrib><creatorcontrib>Huh, J.R</creatorcontrib><creatorcontrib>Seol, J.H</creatorcontrib><creatorcontrib>Yoo, S.J</creatorcontrib><creatorcontrib>Hay, B.A</creatorcontrib><creatorcontrib>Guo, M</creatorcontrib><title>Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin</title><title>Nature</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology1. Recently, multiple genes mediating familial forms of Parkinson's disease have been identified, including PTEN-induced kinase 1 (PINK1 ; PARK6 ) and parkin (PARK2 ), which are also associated with sporadic forms of Parkinson's disease. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence. So far, no in vivo studies have been reported for pink1 in any model system. Here we show that removal of Drosophila PINK1 homologue (CG4523; hereafter called pink1) function results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress. Pink1 localizes to mitochondria, and mitochondrial cristae are fragmented in pink1 mutants. Expression of human PINK1 in the Drosophila testes restores male fertility and normal mitochondrial morphology in a portion of pink1 mutants, demonstrating functional conservation between human and Drosophila Pink1. Loss of Drosophila parkin shows phenotypes similar to loss of pink1 function. Notably, overexpression of parkin rescues the male sterility and mitochondrial morphology defects of pink1 mutants, whereas double mutants removing both pink1 and parkin function show muscle phenotypes identical to those observed in either mutant alone. These observations suggest that pink1 and parkin function, at least in part, in the same pathway, with pink1 functioning upstream of parkin. The role of the pink1-parkin pathway in regulating mitochondrial function underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson's disease pathogenesis.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>cytochemistry</subject><subject>cytopathogenicity</subject><subject>Drosophila</subject><subject>Drosophila melanogaster</subject><subject>Drosophila melanogaster - cytology</subject><subject>Drosophila melanogaster - enzymology</subject><subject>Drosophila melanogaster - genetics</subject><subject>Drosophila melanogaster - physiology</subject><subject>Drosophila Proteins - genetics</subject><subject>Drosophila Proteins - metabolism</subject><subject>Epistasis, Genetic</subject><subject>Fertility</subject><subject>Genetic Complementation Test</subject><subject>Genetics</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Infertility, Male - genetics</subject><subject>Infertility, Male - pathology</subject><subject>Insects</subject><subject>letter</subject><subject>Longevity - genetics</subject><subject>Longevity - physiology</subject><subject>Male</subject><subject>male fertility</subject><subject>Male sterility</subject><subject>mitochondria</subject><subject>Mitochondria - pathology</subject><subject>Mitochondria - physiology</subject><subject>Mitochondrial DNA</subject><subject>multidisciplinary</subject><subject>muscles</subject><subject>Muscles - metabolism</subject><subject>Muscles - pathology</subject><subject>Mutants</subject><subject>Mutation - genetics</subject><subject>Neurological disorders</subject><subject>Neurons</subject><subject>Oxidative stress</subject><subject>parkin</subject><subject>Parkinson Disease - genetics</subject><subject>Parkinson Disease - pathology</subject><subject>Parkinson Disease - physiopathology</subject><subject>Parkinson's disease</subject><subject>Pathology</subject><subject>Phenotype</subject><subject>Protein Kinases - genetics</subject><subject>Protein Kinases - metabolism</subject><subject>Protein Transport</subject><subject>Proteins</subject><subject>PTEN-induced kinase 1</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>spermatids</subject><subject>Spermatids - metabolism</subject><subject>Spermatids - pathology</subject><subject>tissue degeneration</subject><subject>Toxins</subject><subject>Ubiquitin-Protein 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pink1 is required for mitochondrial function and interacts genetically with parkin</title><author>Clark, I.E ; Dodson, M.W ; Jiang, C ; Cao, J.H ; Huh, J.R ; Seol, J.H ; Yoo, S.J ; Hay, B.A ; Guo, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c668t-e09fa0c25e653fe28ad02b5378eee74d7398e53ce5a001c1ac436bc4ae461a6a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Adenosine Triphosphate - metabolism</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>cytochemistry</topic><topic>cytopathogenicity</topic><topic>Drosophila</topic><topic>Drosophila melanogaster</topic><topic>Drosophila melanogaster - cytology</topic><topic>Drosophila melanogaster - enzymology</topic><topic>Drosophila melanogaster - genetics</topic><topic>Drosophila melanogaster - physiology</topic><topic>Drosophila Proteins - genetics</topic><topic>Drosophila Proteins - metabolism</topic><topic>Epistasis, Genetic</topic><topic>Fertility</topic><topic>Genetic Complementation Test</topic><topic>Genetics</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Infertility, Male - genetics</topic><topic>Infertility, Male - pathology</topic><topic>Insects</topic><topic>letter</topic><topic>Longevity - genetics</topic><topic>Longevity - physiology</topic><topic>Male</topic><topic>male fertility</topic><topic>Male sterility</topic><topic>mitochondria</topic><topic>Mitochondria - pathology</topic><topic>Mitochondria - physiology</topic><topic>Mitochondrial DNA</topic><topic>multidisciplinary</topic><topic>muscles</topic><topic>Muscles - metabolism</topic><topic>Muscles - pathology</topic><topic>Mutants</topic><topic>Mutation - genetics</topic><topic>Neurological disorders</topic><topic>Neurons</topic><topic>Oxidative stress</topic><topic>parkin</topic><topic>Parkinson Disease - genetics</topic><topic>Parkinson Disease - pathology</topic><topic>Parkinson Disease - physiopathology</topic><topic>Parkinson's disease</topic><topic>Pathology</topic><topic>Phenotype</topic><topic>Protein Kinases - genetics</topic><topic>Protein Kinases - metabolism</topic><topic>Protein Transport</topic><topic>Proteins</topic><topic>PTEN-induced kinase 1</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>spermatids</topic><topic>Spermatids - metabolism</topic><topic>Spermatids - pathology</topic><topic>tissue degeneration</topic><topic>Toxins</topic><topic>Ubiquitin-Protein Ligases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Clark, I.E</creatorcontrib><creatorcontrib>Dodson, M.W</creatorcontrib><creatorcontrib>Jiang, C</creatorcontrib><creatorcontrib>Cao, J.H</creatorcontrib><creatorcontrib>Huh, J.R</creatorcontrib><creatorcontrib>Seol, J.H</creatorcontrib><creatorcontrib>Yoo, S.J</creatorcontrib><creatorcontrib>Hay, 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parkin</atitle><jtitle>Nature</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2006-06-29</date><risdate>2006</risdate><volume>441</volume><issue>7097</issue><spage>1162</spage><epage>1166</epage><pages>1162-1166</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><eissn>1476-4679</eissn><coden>NATUAS</coden><abstract>Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology1. Recently, multiple genes mediating familial forms of Parkinson's disease have been identified, including PTEN-induced kinase 1 (PINK1 ; PARK6 ) and parkin (PARK2 ), which are also associated with sporadic forms of Parkinson's disease. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence. So far, no in vivo studies have been reported for pink1 in any model system. Here we show that removal of Drosophila PINK1 homologue (CG4523; hereafter called pink1) function results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress. Pink1 localizes to mitochondria, and mitochondrial cristae are fragmented in pink1 mutants. Expression of human PINK1 in the Drosophila testes restores male fertility and normal mitochondrial morphology in a portion of pink1 mutants, demonstrating functional conservation between human and Drosophila Pink1. Loss of Drosophila parkin shows phenotypes similar to loss of pink1 function. Notably, overexpression of parkin rescues the male sterility and mitochondrial morphology defects of pink1 mutants, whereas double mutants removing both pink1 and parkin function show muscle phenotypes identical to those observed in either mutant alone. These observations suggest that pink1 and parkin function, at least in part, in the same pathway, with pink1 functioning upstream of parkin. The role of the pink1-parkin pathway in regulating mitochondrial function underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson's disease pathogenesis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>16672981</pmid><doi>10.1038/nature04779</doi><tpages>5</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0028-0836 |
ispartof | Nature, 2006-06, Vol.441 (7097), p.1162-1166 |
issn | 0028-0836 1476-4687 1476-4679 |
language | eng |
recordid | cdi_proquest_miscellaneous_68595976 |
source | MEDLINE; Nature; Alma/SFX Local Collection |
subjects | Adenosine Triphosphate - metabolism Animals Apoptosis cytochemistry cytopathogenicity Drosophila Drosophila melanogaster Drosophila melanogaster - cytology Drosophila melanogaster - enzymology Drosophila melanogaster - genetics Drosophila melanogaster - physiology Drosophila Proteins - genetics Drosophila Proteins - metabolism Epistasis, Genetic Fertility Genetic Complementation Test Genetics Humanities and Social Sciences Humans Infertility, Male - genetics Infertility, Male - pathology Insects letter Longevity - genetics Longevity - physiology Male male fertility Male sterility mitochondria Mitochondria - pathology Mitochondria - physiology Mitochondrial DNA multidisciplinary muscles Muscles - metabolism Muscles - pathology Mutants Mutation - genetics Neurological disorders Neurons Oxidative stress parkin Parkinson Disease - genetics Parkinson Disease - pathology Parkinson Disease - physiopathology Parkinson's disease Pathology Phenotype Protein Kinases - genetics Protein Kinases - metabolism Protein Transport Proteins PTEN-induced kinase 1 Science Science (multidisciplinary) spermatids Spermatids - metabolism Spermatids - pathology tissue degeneration Toxins Ubiquitin-Protein Ligases |
title | Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T20%3A50%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Drosophila%20pink1%20is%20required%20for%20mitochondrial%20function%20and%20interacts%20genetically%20with%20parkin&rft.jtitle=Nature&rft.au=Clark,%20I.E&rft.date=2006-06-29&rft.volume=441&rft.issue=7097&rft.spage=1162&rft.epage=1166&rft.pages=1162-1166&rft.issn=0028-0836&rft.eissn=1476-4687&rft.coden=NATUAS&rft_id=info:doi/10.1038/nature04779&rft_dat=%3Cgale_proqu%3EA185450017%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=204539464&rft_id=info:pmid/16672981&rft_galeid=A185450017&rfr_iscdi=true |