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1.
J Pathol ; 249(2): 241-254, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31144295

RESUMO

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.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Proteínas F-Box/metabolismo , Mesencéfalo/metabolismo , Degeneração Neural , Doença de Parkinson/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Ribossômicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Comportamento Animal , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Proteínas F-Box/genética , Feminino , Locomoção , Masculino , Mesencéfalo/patologia , Mesencéfalo/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Doença de Parkinson/genética , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Ribossômicas/genética , Transdução de Sinais , Proteína Supressora de Tumor p53/genética
2.
EMBO J ; 35(18): 1963-78, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27354364

RESUMO

Pre-B-cell leukemia homeobox (PBX) transcription factors are known to regulate organogenesis, but their molecular targets and function in midbrain dopaminergic neurons (mDAn) as well as their role in neurodegenerative diseases are unknown. Here, we show that PBX1 controls a novel transcriptional network required for mDAn specification and survival, which is sufficient to generate mDAn from human stem cells. Mechanistically, PBX1 plays a dual role in transcription by directly repressing or activating genes, such as Onecut2 to inhibit lateral fates during embryogenesis, Pitx3 to promote mDAn development, and Nfe2l1 to protect from oxidative stress. Notably, PBX1 and NFE2L1 levels are severely reduced in dopaminergic neurons of the substantia nigra of Parkinson's disease (PD) patients and decreased NFE2L1 levels increases damage by oxidative stress in human midbrain cells. Thus, our results reveal novel roles for PBX1 and its transcriptional network in mDAn development and PD, opening the door for new therapeutic interventions.


Assuntos
Diferenciação Celular , Proteínas de Ligação a DNA/metabolismo , Neurônios Dopaminérgicos/fisiologia , Redes Reguladoras de Genes , Doença de Parkinson/patologia , Proteínas Proto-Oncogênicas/metabolismo , Substância Negra/patologia , Humanos , Fator de Transcrição 1 de Leucemia de Células Pré-B
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