A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction
Abstract Mitochondrial diseases comprise a common group of neurometabolic disorders resulting from OXPHOS defects, that may manifest with neurological impairments, for which there are currently no disease-modifying therapies. Previous studies suggest inhibitory interneuron susceptibility to mitochon...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05238-7 |
| _version_ | 1797557244381888512 |
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| author | Elizaveta A. Olkhova Carla Bradshaw Alasdair Blain Debora Alvim Doug M. Turnbull Fiona E. N. LeBeau Yi Shiau Ng Gráinne S. Gorman Nichola Z. Lax |
| author_facet | Elizaveta A. Olkhova Carla Bradshaw Alasdair Blain Debora Alvim Doug M. Turnbull Fiona E. N. LeBeau Yi Shiau Ng Gráinne S. Gorman Nichola Z. Lax |
| author_sort | Elizaveta A. Olkhova |
| collection | DOAJ |
| description | Abstract Mitochondrial diseases comprise a common group of neurometabolic disorders resulting from OXPHOS defects, that may manifest with neurological impairments, for which there are currently no disease-modifying therapies. Previous studies suggest inhibitory interneuron susceptibility to mitochondrial impairment, especially of parvalbumin-expressing interneurons (PV+). We have developed a mouse model of mitochondrial dysfunction specifically in PV+ cells via conditional Tfam knockout, that exhibited a juvenile-onset progressive phenotype characterised by cognitive deficits, anxiety-like behaviour, head-nodding, stargazing, ataxia, and reduced lifespan. A brain region-dependent decrease of OXPHOS complexes I and IV in PV+ neurons was detected, with Purkinje neurons being most affected. We validated these findings in a neuropathological study of patients with pathogenic mtDNA and POLG variants showing PV+ interneuron loss and deficiencies in complexes I and IV. This mouse model offers a drug screening platform to propel the discovery of therapeutics to treat severe neurological impairment due to mitochondrial dysfunction. |
| first_indexed | 2024-03-10T17:14:40Z |
| format | Article |
| id | doaj.art-d905e99197394a9cbdda0d8fb7b9226c |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-10T17:14:40Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-d905e99197394a9cbdda0d8fb7b9226c2023-11-20T10:33:26ZengNature PortfolioCommunications Biology2399-36422023-10-016111710.1038/s42003-023-05238-7A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunctionElizaveta A. Olkhova0Carla Bradshaw1Alasdair Blain2Debora Alvim3Doug M. Turnbull4Fiona E. N. LeBeau5Yi Shiau Ng6Gráinne S. Gorman7Nichola Z. Lax8Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityBiosciences Institute, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityAbstract Mitochondrial diseases comprise a common group of neurometabolic disorders resulting from OXPHOS defects, that may manifest with neurological impairments, for which there are currently no disease-modifying therapies. Previous studies suggest inhibitory interneuron susceptibility to mitochondrial impairment, especially of parvalbumin-expressing interneurons (PV+). We have developed a mouse model of mitochondrial dysfunction specifically in PV+ cells via conditional Tfam knockout, that exhibited a juvenile-onset progressive phenotype characterised by cognitive deficits, anxiety-like behaviour, head-nodding, stargazing, ataxia, and reduced lifespan. A brain region-dependent decrease of OXPHOS complexes I and IV in PV+ neurons was detected, with Purkinje neurons being most affected. We validated these findings in a neuropathological study of patients with pathogenic mtDNA and POLG variants showing PV+ interneuron loss and deficiencies in complexes I and IV. This mouse model offers a drug screening platform to propel the discovery of therapeutics to treat severe neurological impairment due to mitochondrial dysfunction.https://doi.org/10.1038/s42003-023-05238-7 |
| spellingShingle | Elizaveta A. Olkhova Carla Bradshaw Alasdair Blain Debora Alvim Doug M. Turnbull Fiona E. N. LeBeau Yi Shiau Ng Gráinne S. Gorman Nichola Z. Lax A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction Communications Biology |
| title | A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction |
| title_full | A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction |
| title_fullStr | A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction |
| title_full_unstemmed | A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction |
| title_short | A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction |
| title_sort | novel mouse model of mitochondrial disease exhibits juvenile onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction |
| url | https://doi.org/10.1038/s42003-023-05238-7 |
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