Loss of FBXO7 results in a Parkinson’s-like dopaminergic degeneration via an RPL23-MDM2-TP53 pathway
| Autor: | Stott, Simon, Randle, Suzanne, Al Rawi, Sara, Rowicka, Paulina, Harris, Rebecca, Mason, Bethany, Xia, Jing, Dalley, Jeffrey, Barker, Roger, Laman, Heike |
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| Přispěvatelé: | Harris, Rebecca [0000-0002-5854-4700], Mason, Bethany [0000-0002-1157-0469], Dalley, Jeffrey [0000-0002-2282-3660], Barker, Roger [0000-0001-8843-7730], Laman, Heike [0000-0002-6089-171X], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
Male
Mice Knockout Ribosomal Proteins dopaminergic neurons Behavior Animal Parkinson's disease F-Box Proteins Parkinson Disease Proto-Oncogene Proteins c-mdm2 Motor Activity Rpl23-Mdm2-p53 axis Mice Inbred C57BL Disease Models Animal nervous system Mesencephalon Nerve Degeneration Animals Female Tumor Suppressor Protein p53 FBXO7/PARK15 Locomotion Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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