RESUMEN
Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson's disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants (P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD.
Asunto(s)
Encéfalo/metabolismo , Neuronas Dopaminérgicas/metabolismo , Mutación , Proteínas del Tejido Nervioso/genética , Enfermedad de Parkinson/genética , Receptores de Superficie Celular/genética , Adulto , Edad de Inicio , Animales , Apoptosis/genética , Translocador Nuclear del Receptor de Aril Hidrocarburo/antagonistas & inhibidores , Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Translocador Nuclear del Receptor de Aril Hidrocarburo/metabolismo , Secuencia de Bases , Encéfalo/patología , Estudios de Casos y Controles , Estudios de Cohortes , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/patología , Proteínas de Drosophila/antagonistas & inhibidores , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Diagnóstico Precoz , Femenino , Expresión Génica , Redes Reguladoras de Genes , Humanos , Masculino , Proteínas del Tejido Nervioso/metabolismo , Padres , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores de Superficie Celular/metabolismo , HermanosRESUMEN
Previous studies have documented that orphan nuclear receptor Nurr1 (also known as NR4A2) plays important roles in the midbrain dopamine (DA) neuron development, differentiation, and survival. Furthermore, it has been reported that the defects in Nurr1 are associated with Parkinson's disease (PD). Thus, Nurr1 might be a potential therapeutic target for PD. Emerging evidence from in vitro and in vivo studies has recently demonstrated that Nurr1-activating compounds and Nurr1 gene therapy are able not only to enhance DA neurotransmission but also to protect DA neurons from cell injury induced by environmental toxin or microglia-mediated neuroinflammation. Moreover, modulators that interact with Nurr1 or regulate its function, such as retinoid X receptor, cyclic AMP-responsive element-binding protein, glial cell line-derived neurotrophic factor, and Wnt/ß-catenin pathway, have the potential to enhance the effects of Nurr1-based therapies in PD. This review highlights the recent progress in preclinical studies of Nurr1-based therapies and discusses the outlook of this emerging therapy as a promising new generation of PD medication.