RESUMEN
The orphan nuclear receptor Nurr1 is critical for the development, maintenance, and protection of midbrain dopaminergic neurons. Recently, we demonstrated that prostaglandins E1 (PGE1) and PGA1 directly bind to the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional activation function. In this direction, here we report the transcriptional activation of Nurr1 by PGA2, a dehydrated metabolite of PGE2, through physical binding ably supported by NMR titration and crystal structure. The co-crystal structure of Nurr1-LBD bound to PGA2 revealed the covalent coupling of PGA2 with Nurr1-LBD through Cys566. PGA2 binding also induces a 21° shift of the activation function 2 (AF-2) helix H12 away from the protein core, similar to that observed in the Nurr1-LBD-PGA1 complex. We also show that PGA2 can rescue the locomotor deficits and neuronal degeneration in LRRK2 G2019S transgenic fly models.
Asunto(s)
Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Enfermedad de Parkinson , Prostaglandinas A , Humanos , Ligandos , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Prostaglandinas A/genética , Prostaglandinas A/metabolismo , Animales Modificados Genéticamente , Drosophila , Modelos Animales de EnfermedadRESUMEN
A myriad of chemical modifications of DNA and histones involved in the epigenetic regulation of neural gene expression have been documented and studied in detail since many years. However, more recently, modifications in RNA and their implications for neural gene functions have been progressively investigated. Of these, the most widely studied is the N6-methyladenosine (m6A) modification. The discovery of the first m6A demethylase, known as the fat, mass and obesity (FTO) associated protein, has further fortified the field of epitranscriptomic regulatory mechanisms, owing to FTO's involvement in several biological processes including brain development and function. Concomitantly, multiple lines of evidence have associated FTO with neuropsychiatric disorders. In this review, we discuss how FTO can exert its effect by acting not only on m6A but also on O, N6-dimethyladenosine (m6Am) in different types of RNA and potentially influence the development of some major neuropsychiatric diseases.