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A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction

Lookup NU author(s): Dr Elizaveta Olkhova, Carla Bradshaw, Emeritus Professor Doug Turnbull, Dr Fiona LeBeauORCiD, Dr Yi NgORCiD, Professor Grainne Gorman, Dr Nichola Lax

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2023, Springer Nature Limited. 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.

Publication metadata

Author(s): Olkhova EA, Bradshaw C, Blain A, Alvim D, Turnbull DM, LeBeau FEN, Ng YS, Gorman GS, Lax NZ

Publication type: Article

Publication status: Published

Journal: Communications Biology

Year: 2023

Volume: 6

Issue: 1

Online publication date: 23/10/2023

Acceptance date: 10/08/2023

Date deposited: 08/11/2023

ISSN (electronic): 2399-3642

Publisher: Springer Nature

URL: https://doi.org/10.1038/s42003-023-05238-7

DOI: 10.1038/s42003-023-05238-7

Data Access Statement: All source data for figures is provided in the Supplementary Data file.

PubMed id: 37872380

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