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

Elena Vezzoli; Ilaria Caron; Francesca Talpo; Dario Besusso; Paola Conforti; Elisa Battaglia; Elisa Sogne; Andrea Falqui; Lara Petricca; Margherita Verani; Paola Martufi; Andrea Caricasole; Alberto Bresciani; Ottavia Cecchetti; Pia Rivetti di Val Cervo; Giulio Sancini; Olaf Riess; Hoa Nguyen; Lisa Seipold; Paul Saftig; Gerardo Biella; Elena Cattaneo; Chiara Zuccato

doi:10.1172/jci120616

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

Elena Vezzoli, Ilaria Caron, Francesca Talpo, Dario Besusso, Paola Conforti, Elisa Battaglia, Elisa Sogne, Andrea Falqui, Lara Petricca, Margherita Verani, Paola Martufi, Andrea Caricasole, Alberto Bresciani, Ottavia Cecchetti, Pia Rivetti di Val Cervo, Giulio Sancini, Olaf Riess, Hoa Nguyen, Lisa Seipold, Paul SaftigGerardo Biella, Elena Cattaneo, Chiara Zuccato

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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.

Original language	English (US)
Pages (from-to)	2390-2403
Number of pages	14
Journal	Journal of Clinical Investigation
Volume	129
Issue number	6
DOIs	https://doi.org/10.1172/jci120616
State	Published - May 6 2019

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: This study was supported by grants from Telethon (GGP13053) to CZ and from the Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica, Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale to CZ and GS (20128XWKTX); from Neuromics (305121), ModelPolyQ (JPCOFUND-643417), and CircProt (JPCOFUND-643417) to EC; from the Deutsche Forschungsgemeinschaft (DFG-SFB877-A3) to PS; from the Interuniversity Attraction Poles (IAP-P5) and the Breuer Foundation Research Award to PS and ES; and from KAUST baseline funding to AF. AB, AC, LP, MV, PM, and OC were supported by CNCCS Scarl. We acknowledge the CHDI Foundation for zQ175 mice and NOLIMITS, an advanced imaging facility established by the Università degli Studi di Milano. We thank the Italian HD patients and families for their closeness and trust.

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https://repository.kaust.edu.sa/bitstream/10754/652854/2/120616.1-20190503181339-covered-253bed37ca4c1ab43d105aefdf7b5536.pdf

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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., ... Zuccato, C. (2019). Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease. Journal of Clinical Investigation, 129(6), 2390-2403. https://doi.org/10.1172/jci120616

@article{ed4461f410424ecaa15cef5706550ab4,

title = "Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington{\textquoteright}s disease",

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.",

author = "Elena Vezzoli and Ilaria Caron and Francesca Talpo and Dario Besusso and Paola Conforti and Elisa Battaglia and Elisa Sogne and Andrea Falqui and Lara Petricca and Margherita Verani and Paola Martufi and Andrea Caricasole and Alberto Bresciani and Ottavia Cecchetti and {Rivetti di Val Cervo}, Pia and Giulio Sancini and Olaf Riess and Hoa Nguyen and Lisa Seipold and Paul Saftig and Gerardo Biella and Elena Cattaneo and Chiara Zuccato",

note = "KAUST Repository Item: Exported on 2020-10-01 Acknowledgements: This study was supported by grants from Telethon (GGP13053) to CZ and from the Ministero dell{\textquoteright}Istruzione, dell{\textquoteright}Universit{\`a} e della Ricerca Scientifica, Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale to CZ and GS (20128XWKTX); from Neuromics (305121), ModelPolyQ (JPCOFUND-643417), and CircProt (JPCOFUND-643417) to EC; from the Deutsche Forschungsgemeinschaft (DFG-SFB877-A3) to PS; from the Interuniversity Attraction Poles (IAP-P5) and the Breuer Foundation Research Award to PS and ES; and from KAUST baseline funding to AF. AB, AC, LP, MV, PM, and OC were supported by CNCCS Scarl. We acknowledge the CHDI Foundation for zQ175 mice and NOLIMITS, an advanced imaging facility established by the Universit{\`a} degli Studi di Milano. We thank the Italian HD patients and families for their closeness and trust.",

year = "2019",

month = may,

day = "6",

doi = "10.1172/jci120616",

language = "English (US)",

volume = "129",

pages = "2390--2403",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "6",

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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 & Zuccato, C 2019, 'Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease', Journal of Clinical Investigation, vol. 129, no. 6, pp. 2390-2403. https://doi.org/10.1172/jci120616

TY - JOUR

T1 - Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease

AU - Vezzoli, Elena

AU - Caron, Ilaria

AU - Talpo, Francesca

AU - Besusso, Dario

AU - Conforti, Paola

AU - Battaglia, Elisa

AU - Sogne, Elisa

AU - Falqui, Andrea

AU - Petricca, Lara

AU - Verani, Margherita

AU - Martufi, Paola

AU - Caricasole, Andrea

AU - Bresciani, Alberto

AU - Cecchetti, Ottavia

AU - Rivetti di Val Cervo, Pia

AU - Sancini, Giulio

AU - Riess, Olaf

AU - Nguyen, Hoa

AU - Seipold, Lisa

AU - Saftig, Paul

AU - Biella, Gerardo

AU - Cattaneo, Elena

AU - Zuccato, Chiara

N1 - KAUST Repository Item: Exported on 2020-10-01 Acknowledgements: This study was supported by grants from Telethon (GGP13053) to CZ and from the Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica, Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale to CZ and GS (20128XWKTX); from Neuromics (305121), ModelPolyQ (JPCOFUND-643417), and CircProt (JPCOFUND-643417) to EC; from the Deutsche Forschungsgemeinschaft (DFG-SFB877-A3) to PS; from the Interuniversity Attraction Poles (IAP-P5) and the Breuer Foundation Research Award to PS and ES; and from KAUST baseline funding to AF. AB, AC, LP, MV, PM, and OC were supported by CNCCS Scarl. We acknowledge the CHDI Foundation for zQ175 mice and NOLIMITS, an advanced imaging facility established by the Università degli Studi di Milano. We thank the Italian HD patients and families for their closeness and trust.

PY - 2019/5/6

Y1 - 2019/5/6

N2 - 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.

AB - 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.

UR - http://hdl.handle.net/10754/652854

UR - https://www.jci.org/articles/view/120616

UR - http://www.scopus.com/inward/record.url?scp=85065796746&partnerID=8YFLogxK

U2 - 10.1172/jci120616

DO - 10.1172/jci120616

M3 - Article

C2 - 31063986

SN - 0021-9738

VL - 129

SP - 2390

EP - 2403

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 6

ER -

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

Abstract

Bibliographical note

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