1. Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease
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Margherita Verani, Olaf Riess, Alberto Bresciani, Paola Martufi, Gerardo Biella, Paul Saftig, Elena Vezzoli, Francesca Talpo, Giulio Sancini, Ottavia Cecchetti, Paola Conforti, Andrea Falqui, Pia Rivetti di Val Cervo, Elisa Sogne, Lisa Seipold, Hoa Nguyen, Chiara Zuccato, Dario Besusso, Elena Cattaneo, Lara Petricca, Ilaria Caron, Andrea Caricasole, Elisa Battaglia, Vezzoli, E, Caron, I, Talpo, F, Besusso, D, Conforti, P, Battaglia, E, Sogne, E, Falqui, A, Petricca, L, Verani, M, Martufi, P, Caricasole, A, Bresciani, A, Cecchetti, O, Rivetti di Val Cervo, P, Sancini, G, Riess, O, Nguyen, H, Seipold, L, Saftig, P, Biella, G, Cattaneo, E, and Zuccato, C
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Adult ,Male ,0301 basic medicine ,Huntingtin ,ADAM10 ,Mice, Transgenic ,Biology ,Synapse ,ADAM10 Protein ,03 medical and health sciences ,0302 clinical medicine ,Huntington's disease ,Antigens, CD ,Postsynaptic potential ,BIO/09 - FISIOLOGIA ,medicine ,Animals ,Humans ,Gene silencing ,Cognitive Dysfunction ,Cognitive decline ,Neurodegeneration ,Receptor ,Aged ,Medicine (all) ,Membrane Proteins ,Post-Synaptic Density ,General Medicine ,Middle Aged ,Cadherins ,medicine.disease ,3. Good health ,Cell biology ,Disease Models, Animal ,HEK293 Cells ,Huntington Disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,Amyloid Precursor Protein Secretases ,Neuroscience - Abstract
A disintegrine and metalloproteinase 10 (ADAM10) is implicated in synaptic function through its interaction with postsynaptic receptors and adhesion molecules. Here, we report that levels of active ADAM10 are increased in Huntington's disease (HD) mouse cortices and striata and in human postmortem caudate. We show that, in the presence of polyglutamine-expanded (polyQ-expanded) huntingtin (HTT), ADAM10 accumulates at the postsynaptic densities (PSDs) and causes excessive cleavage of the synaptic protein N-cadherin (N-CAD). This aberrant phenotype is also detected in neurons from HD patients where it can be reverted by selective silencing of mutant HTT. Consistently, ex vivo delivery of an ADAM10 synthetic inhibitor reduces N-CAD proteolysis and corrects electrophysiological alterations in striatal medium-sized spiny neurons (MSNs) of 2 HD mouse models. Moreover, we show that heterozygous conditional deletion of ADAM10 or delivery of a competitive TAT-Pro-ADAM10709-729 peptide in R6/2 mice prevents N-CAD proteolysis and ameliorates cognitive deficits in the mice. Reduction in synapse loss was also found in R6/2 mice conditionally deleted for ADAM10. Taken together, these results point to a detrimental role of hyperactive ADAM10 at the HD synapse and provide preclinical evidence of the therapeutic potential of ADAM10 inhibition in HD.
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