1. A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction.
- Author
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Olkhova, Elizaveta A., Bradshaw, Carla, Blain, Alasdair, Alvim, Debora, Turnbull, Doug M., LeBeau, Fiona E. N., Ng, Yi Shiau, Gorman, Gráinne S., and Lax, Nichola Z.
- Subjects
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LABORATORY mice , *INTERNEURONS , *ANIMAL disease models , *MITOCHONDRIA , *JUVENILE diseases , *MITOCHONDRIAL DNA , *COGNITIVE computing - 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. The establishment of a mouse model of mitochondrial dysfunction in parvalbumin-expressing interneurons, resembling mitochondrial and cognitive defects observed in patients, provides a route for drug screening towards a therapeutic avenue for neurological impairment. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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