Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease
Rivetti di Val Cervo, Pia
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Online Publication Date2019-05-06
Print Publication Date2019-05-06
Permanent link to this recordhttp://hdl.handle.net/10754/652854
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AbstractA 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.
CitationVezzoli E, Caron I, Talpo F, Besusso D, Conforti P, et al. (2019) Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease. Journal of Clinical Investigation. Available: http://dx.doi.org/10.1172/jci120616.
SponsorsThis 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.