Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration.
<h4>Background</h4>Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD.&l...
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2009
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oai:doaj.org-article:45f68ab49b2d403fa1646e411e62f4332021-11-25T06:22:20ZParkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration.1932-620310.1371/journal.pone.0005777https://doaj.org/article/45f68ab49b2d403fa1646e411e62f4332009-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19492057/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD.<h4>Methodology/principal findings</h4>Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons.<h4>Conclusion</h4>Thus, aging Pink1(-/-) mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.Suzana GispertFilomena RicciardiAlexander KurzMekhman AzizovHans-Hermann HoepkenDorothea BeckerWolfgang VoosKristina LeunerWalter E MüllerAlexei P KudinWolfram S KunzAnnabelle ZimmermannJochen RoeperDirk WenzelMarina JendrachMoisés García-ArencíbiaJavier Fernández-RuizLeslie HuberHermann RohrerMiguel BarreraAndreas S ReichertUdo RübAmy ChenRobert L NussbaumGeorg AuburgerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 6, p e5777 (2009) |
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Medicine R Science Q Suzana Gispert Filomena Ricciardi Alexander Kurz Mekhman Azizov Hans-Hermann Hoepken Dorothea Becker Wolfgang Voos Kristina Leuner Walter E Müller Alexei P Kudin Wolfram S Kunz Annabelle Zimmermann Jochen Roeper Dirk Wenzel Marina Jendrach Moisés García-Arencíbia Javier Fernández-Ruiz Leslie Huber Hermann Rohrer Miguel Barrera Andreas S Reichert Udo Rüb Amy Chen Robert L Nussbaum Georg Auburger Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. |
| description |
<h4>Background</h4>Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD.<h4>Methodology/principal findings</h4>Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons.<h4>Conclusion</h4>Thus, aging Pink1(-/-) mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death. |
| format |
article |
| author |
Suzana Gispert Filomena Ricciardi Alexander Kurz Mekhman Azizov Hans-Hermann Hoepken Dorothea Becker Wolfgang Voos Kristina Leuner Walter E Müller Alexei P Kudin Wolfram S Kunz Annabelle Zimmermann Jochen Roeper Dirk Wenzel Marina Jendrach Moisés García-Arencíbia Javier Fernández-Ruiz Leslie Huber Hermann Rohrer Miguel Barrera Andreas S Reichert Udo Rüb Amy Chen Robert L Nussbaum Georg Auburger |
| author_facet |
Suzana Gispert Filomena Ricciardi Alexander Kurz Mekhman Azizov Hans-Hermann Hoepken Dorothea Becker Wolfgang Voos Kristina Leuner Walter E Müller Alexei P Kudin Wolfram S Kunz Annabelle Zimmermann Jochen Roeper Dirk Wenzel Marina Jendrach Moisés García-Arencíbia Javier Fernández-Ruiz Leslie Huber Hermann Rohrer Miguel Barrera Andreas S Reichert Udo Rüb Amy Chen Robert L Nussbaum Georg Auburger |
| author_sort |
Suzana Gispert |
| title |
Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. |
| title_short |
Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. |
| title_full |
Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. |
| title_fullStr |
Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. |
| title_full_unstemmed |
Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. |
| title_sort |
parkinson phenotype in aged pink1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2009 |
| url |
https://doaj.org/article/45f68ab49b2d403fa1646e411e62f433 |
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