Carulla P.,Cellular Bioengineering |
Carulla P.,University of Barcelona |
Carulla P.,Center for Biomedical Research in Neurodegenerative Diseases |
Bribian A.,Cellular Bioengineering |
And 18 more authors.
Molecular Biology of the Cell | Year: 2011
Cellular prion protein (PrP C) is a glycosyl- phosphatidylinositol-anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrP SC) induces transmissible spongiform encephalopathies. In contrast, PrP C has a number of physiological functions in several neural processes. Several lines of evidence implicate PrP C in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrP C has been implicated in the inhibition of N-methyl-d-aspartic acid (NMDA)-mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnp o/ oJnk3 o/ omice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrP C-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrP C with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6-PSD-95 interaction after KA injections was favored by the absence of PrP C. Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3- dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrP C against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation. © 2011 Carulla et al. Source
Fernandez-Santiago R.,University of Barcelona |
Fernandez-Santiago R.,Center for Biomedical Research in Neurodegenerative Diseases |
Iranzo A.,Center for Biomedical Research in Neurodegenerative Diseases |
Iranzo A.,University of Barcelona |
And 12 more authors.
Annals of Neurology | Year: 2015
Recently, we reported downregulated circulating levels of the microRNAs miR-19b, miR-29a, and miR-29c in Parkinson disease. Here we investigated the expression of these microRNAs in serum samples from 56 patients with idiopathic rapid eye movement sleep behavior disorder, before and after their conversion into a synucleinopathy. Compared to controls, we found that the expression level of miR-19b is downregulated in patients with idiopathic rapid eye movement sleep behavior disorder and antedates the diagnosis of Parkinson disease and dementia with Lewy bodies after 4.67 ± 2.61 years of follow-up. Our findings indicate that dysregulation of the microRNA miR-19b occurs in the prodromal stage of synucleinopathies. Ann Neurol 2015;77:895-901 © 2015 American Neurological Association. Source