title: PKC Activation Counteracts ADAM10 Deficit in HuD-Silenced Neuroblastoma Cells.
abstract: Neuronal ELAV/Hu (nELAV) are RNA-binding proteins that mainly regulate gene expression by increasing the stability and/or translation rate of target mRNAs bearing ARE (adenine and uracil-rich elements) sequences. Among nELAV target transcripts there is ADAM10, an α-secretase involved in the non-amyloidogenic processing of the amyloid-β protein precursor (AβPP) which leads to the production of the neuroprotective sAβPPα peptide. The aim of this study was to evaluate if nELAV depletion affects ADAM10 expression in human SH-SY5Y neuroblastoma cells. We also studied the effects of Bryostatin-1, a molecule able to activate nELAV protein cascade. The specific HuD/nELAV gene silencing decreased both nELAV and ADAM10 protein contents; similar results were obtained by Aβ40 treatment in wild-type SH-SY5Y cells. In HuD-silenced cells, the exposure to Bryostatin-1 counteracted both nELAV and ADAM10 proteins downregulation, by restoring nELAV/ADAM10 basal levels. We also found that sAβPPα release, which seemed not to be compromised by Aβ40 challenge or HuD-silencing, was favored by Bryostatin-1. Overall, these findings strongly suggest that a deficiency in nELAV content negatively affects ADAM10 expression and may play a role in neurodegenerative diseases, which may benefit by molecules activating ELAV cascade.
authors.affiliation: Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Marchesi
authors.affiliation: Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy.
authors.forename: Marialaura
authors.initials: M
authors.lastname: Amadio
authors.affiliation: Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.|Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, University of Milan, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Colombrita
authors.affiliation: Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Govoni
authors.affiliation: Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.|Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, University of Milan, Milan, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Ratti
authors.affiliation: Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Pascale
mesh_terms: D000072197:ADAM10 Protein / Q000172:deficiency* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000633:toxicity; D045744:Cell Line, Tumor; D000067780:ELAV-Like Protein 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000633:toxicity; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D008565:Membrane Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D011493:Protein Kinase C; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human
keywords: ADAM10; Bryostatin-1; HuD silencing; amyloid-β; nELAV; sAβPPα