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.

Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease / E. Vezzoli, I. Caron, F. Talpo, D. Besusso, P. Conforti, E. Battaglia, E. Sogne, A. Falqui, L. Petricca, M. Verani, P. Martufi, A. Caricasole, A. Bresciani, O. Cecchetti, P.R. Di Val Cervo, G. Sancini, O. Riess, H. Nguyen, L. Seipold, P. Saftig, G. Biella, E. Cattaneo, C. Zuccato. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 129:6(2019 Jun), pp. 2390-2403. [10.1172/JCI120616]

Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease

E. Vezzoli
Primo
;
I. Caron;D. Besusso;P. Conforti;A. Falqui;E. Cattaneo;C. Zuccato
2019

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.
Neurodegeneration; Neuroscience; Synapses
Settore BIO/14 - Farmacologia
Settore FIS/01 - Fisica Sperimentale
   Integrated European omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases
   NEUROMICS
   EUROPEAN COMMISSION
   FP7
   305121

   Synaptic CIRCuit PROTection in AD and HD: BDNF and Trkb signaling as rescue factors (CircProt)
   CircProt
   MINISTERO DELL'ISTRUZIONE E DEL MERITO

   Role of ADAM10 in Huntinton Disease
   FONDAZIONE TELETHON ETS
   GGP13053
giu-2019
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/652474
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