Loss of FBXO7 results in a Parkinson's-like dopaminergic degeneration via an RPL23–MDM2–TP53 pathway


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Abstract

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 inFBXO7/PARK15are associated with both sporadic Parkinson's disease and a severe form of autosomal recessive early-onset Parkinsonism. Here we report that conditional deletion ofFbxo7in 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 that the neuroprotective role of FBXO7 involves its suppression of the RPL23–MDM2–p53 axis that promotes cell death in dopaminergic midbrain neurons. © 2019 The Authors.The Journal of Pathologypublished by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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