Loss of FBXO7 results in a Parkinson's-like dopaminergic degeneration via an RPL23-MDM2-TP53 pathway.
J Pathol
; 249(2): 241-254, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-31144295
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 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 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 Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Texto completo:
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Bases de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
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Proteínas Ribossômicas
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Mesencéfalo
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Proteína Supressora de Tumor p53
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Proteínas F-Box
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Proteínas Proto-Oncogênicas c-mdm2
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Neurônios Dopaminérgicos
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Degeneração Neural
Limite:
Animals
Idioma:
En
Revista:
J Pathol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Reino Unido