Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice
Cells rely on efficient protein quality control systems (PQCs) to maintain proper activity of mitochondrial proteins. As part of this system, the mitochondrial chaperone Hsp60 assists folding of matrix proteins and it is an essential protein in all organisms. Mutations in Hspd1, the gene encoding Hs...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-06-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996113000740 |
| _version_ | 1818724944808247296 |
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| author | Raffaella Magnoni Johan Palmfeldt Jane H. Christensen Majken Sand Francesca Maltecca Thomas J. Corydon Mark West Giorgio Casari Peter Bross |
| author_facet | Raffaella Magnoni Johan Palmfeldt Jane H. Christensen Majken Sand Francesca Maltecca Thomas J. Corydon Mark West Giorgio Casari Peter Bross |
| author_sort | Raffaella Magnoni |
| collection | DOAJ |
| description | Cells rely on efficient protein quality control systems (PQCs) to maintain proper activity of mitochondrial proteins. As part of this system, the mitochondrial chaperone Hsp60 assists folding of matrix proteins and it is an essential protein in all organisms. Mutations in Hspd1, the gene encoding Hsp60, are associated with two human inherited diseases of the nervous system, a dominantly inherited form of spastic paraplegia (SPG13) and an autosomal recessively inherited white matter disorder termed MitCHAP60 disease. Although the connection between mitochondrial failure and neurodegeneration is well known in many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, and hereditary spastic paraplegia, the molecular basis of the neurodegeneration associated with these diseases is still ill-defined.Here, we investigate mice heterozygous for a knockout allele of the Hspd1 gene encoding Hsp60. Our results demonstrate that Hspd1 haploinsufficiency is sufficient to cause a late onset and slowly progressive deficit in motor functions in mice. We furthermore emphasize the crucial role of the Hsp60 chaperone in mitochondrial function by showing that the motor phenotype is associated with morphological changes of mitochondria, deficient ATP synthesis, and in particular, a defect in the assembly of the respiratory chain complex III in neuronal tissues. In the current study, we propose that our heterozygous Hsp60 mouse model is a valuable model system for the investigation of the link between mitochondrial dysfunction and neurodegeneration. |
| first_indexed | 2024-12-17T21:34:28Z |
| format | Article |
| id | doaj.art-91b06909bdc747fc8009aca9d0a4d561 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T21:34:28Z |
| publishDate | 2013-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-91b06909bdc747fc8009aca9d0a4d5612022-12-21T21:31:47ZengElsevierNeurobiology of Disease1095-953X2013-06-01541223Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in miceRaffaella Magnoni0Johan Palmfeldt1Jane H. Christensen2Majken Sand3Francesca Maltecca4Thomas J. Corydon5Mark West6Giorgio Casari7Peter Bross8Research Unit for Molecular Medicine, Department of Clinical Medicine, Health Aarhus University Hospital and Aarhus University, Aarhus, Denmark; Corresponding author at: Research Unit for Molecular Medicine, University Hospital and Faculty of Health Sciences, Aarhus University, Brendstrupgaardsvej, DK-8200 Aarhus N, Denmark. Fax: +45 86278402.Research Unit for Molecular Medicine, Department of Clinical Medicine, Health Aarhus University Hospital and Aarhus University, Aarhus, DenmarkDepartment of Biomedicine, Health, Aarhus University, Aarhus, DenmarkDepartment of Biomedicine, Health, Aarhus University, Aarhus, DenmarkVita-Salute San Raffaele University and Centre for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, ItalyDepartment of Biomedicine, Health, Aarhus University, Aarhus, DenmarkDepartment of Biomedicine, Health, Aarhus University, Aarhus, DenmarkVita-Salute San Raffaele University and Centre for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, ItalyResearch Unit for Molecular Medicine, Department of Clinical Medicine, Health Aarhus University Hospital and Aarhus University, Aarhus, DenmarkCells rely on efficient protein quality control systems (PQCs) to maintain proper activity of mitochondrial proteins. As part of this system, the mitochondrial chaperone Hsp60 assists folding of matrix proteins and it is an essential protein in all organisms. Mutations in Hspd1, the gene encoding Hsp60, are associated with two human inherited diseases of the nervous system, a dominantly inherited form of spastic paraplegia (SPG13) and an autosomal recessively inherited white matter disorder termed MitCHAP60 disease. Although the connection between mitochondrial failure and neurodegeneration is well known in many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, and hereditary spastic paraplegia, the molecular basis of the neurodegeneration associated with these diseases is still ill-defined.Here, we investigate mice heterozygous for a knockout allele of the Hspd1 gene encoding Hsp60. Our results demonstrate that Hspd1 haploinsufficiency is sufficient to cause a late onset and slowly progressive deficit in motor functions in mice. We furthermore emphasize the crucial role of the Hsp60 chaperone in mitochondrial function by showing that the motor phenotype is associated with morphological changes of mitochondria, deficient ATP synthesis, and in particular, a defect in the assembly of the respiratory chain complex III in neuronal tissues. In the current study, we propose that our heterozygous Hsp60 mouse model is a valuable model system for the investigation of the link between mitochondrial dysfunction and neurodegeneration.http://www.sciencedirect.com/science/article/pii/S0969996113000740Hereditary spastic paraplegiaAnimal modelHeat shock proteinMitochondrial dysfunctionNeurodegenerative disorders |
| spellingShingle | Raffaella Magnoni Johan Palmfeldt Jane H. Christensen Majken Sand Francesca Maltecca Thomas J. Corydon Mark West Giorgio Casari Peter Bross Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice Neurobiology of Disease Hereditary spastic paraplegia Animal model Heat shock protein Mitochondrial dysfunction Neurodegenerative disorders |
| title | Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice |
| title_full | Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice |
| title_fullStr | Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice |
| title_full_unstemmed | Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice |
| title_short | Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice |
| title_sort | late onset motoneuron disorder caused by mitochondrial hsp60 chaperone deficiency in mice |
| topic | Hereditary spastic paraplegia Animal model Heat shock protein Mitochondrial dysfunction Neurodegenerative disorders |
| url | http://www.sciencedirect.com/science/article/pii/S0969996113000740 |
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