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J Clin Invest. 2019 May 6;130. pii: 120616. doi: 10.1172/JCI120616. eCollection 2019 May 6.

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

Author information

1
Department of Biosciences, University of Milan, Milan, Italy.
2
Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milan, Italy.
3
Department of Biology and Biotechnologies, University of Pavia, Pavia, Italy.
4
King Abdullah University of Science and Technology (KAUST), Biological and Environmental Science & Engineering (BESE) Division, NABLA Lab, Thuwal, Saudi Arabia.
5
IRBM Science Park SpA, Pomezia, Italy.
6
School of Medicine and Surgery, Nanomedicine Center, Neuroscience Center, University of Milano-Bicocca, Monza, Italy.
7
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
8
Institute of Biochemistry, Christian Albrechts University of Kiel, Kiel, Germany.

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.

KEYWORDS:

Neurodegeneration; Neuroscience; Synapses

PMID:
31063986
DOI:
10.1172/JCI120616
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