Loss of FBXO7 results in a Parkinson's-like dopaminergic degeneration via an RPL23-MDM2-TP53 pathway.
Stott, Simon Rw
Randle, Suzanne J
Al Rawi, Sara
Rowicka, Paulina A
The Journal of pathology
John Wiley & Sons Inc.
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Stott, S. R., Randle, S. J., Al Rawi, S., Rowicka, P. A., Harris, R., Mason, B., Xia, J., et al. (2019). Loss of FBXO7 results in a Parkinson's-like dopaminergic degeneration via an RPL23-MDM2-TP53 pathway.. The Journal of pathology, 249 (2), 241-254. https://doi.org/10.1002/path.5312
The field of Parkinson’s disease research has been impeded by the absence of animal models that clearly phenocopy the features of this neurodegenerative condition. Mutations in FBXO7/PARK15 are associated with both sporadic Parkinson’s disease and a severe form of autosomal recessive early-onset Parkinsonism. Here we report that conditional deletion of Fbxo7 in the midbrain dopamine neurons results in an early reduction in striatal dopamine levels, together with a slow, progressive loss of midbrain dopamine neurons and onset of locomotor defects. Unexpectedly, a later compensatory response led to a near-full restoration of dopaminergic fibre innervation in the striatum, but nigral cell loss was irreversible. Mechanistically, there was increased expression in the dopamine neurons of FBXO7-interacting protein, RPL23, which is a sensor of ribosomal stress that inhibits MDM2, the negative regulator of p53. A corresponding activated p53 transcriptional signature biased towards pro-apoptotic genes was also observed. These data suggest the neuroprotective role of FBXO7 involves its suppression of the RPL23-MDM2-p53 axis that promotes cell death in dopaminergic midbrain neurons.
Biotechnology and Biological Sciences Research Council (BB/J007846/1), DDPDgenes, Parkinson's UK and the CurePD Trust, and Wellcome Trust-MRC funded Cambridge Stem Cell Institute and an NIHR award of a Biomedical Research Centre for Addenbrooke’s Hospital/University of Cambridge.
Royal Society (RG2010/R2)
Rosetrees Trust (A784)
Parkinson's UK (G-1701)
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External DOI: https://doi.org/10.1002/path.5312
This record's URL: https://www.repository.cam.ac.uk/handle/1810/292689
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