Affiliations: [a] Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy | [b] Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy | [c] Department of Pathophysiology and Transplantation, ‘Dino Ferrari’ Center, University of Milan, Milan, Italy
Correspondence:
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Correspondence to: Marialaura Amadio, Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy. Tel.: +39 0382 987888; Fax: +39 0382 987405; E-mail: amadio@unipv.it and Alessia Pascale, Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy. Tel.: +39 0382 987230; Fax: +39 0382 987405; E-mail: alessia.pascale@unipv.it.
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.
