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- Title
A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction.
- Authors
Olkhova, Elizaveta A.; Bradshaw, Carla; Blain, Alasdair; Alvim, Debora; Turnbull, Doug M.; LeBeau, Fiona E. N.; Ng, Yi Shiau; Gorman, Gráinne S.; Lax, Nichola Z.
- 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.
- Subjects
LABORATORY mice; INTERNEURONS; ANIMAL disease models; MITOCHONDRIA; JUVENILE diseases; MITOCHONDRIAL DNA; COGNITIVE computing
- Publication
Communications Biology, 2023, Vol 6, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-023-05238-7