A09 ADAM10 activity at the huntington’s disease presynapse

Background ADAM10 is a major protease of the human brain and regulates the strength and activity of the glutamatergic synapse by cleaving a large repertoire of synaptic substrates. In Huntington’s Disease (HD), active ADAM10 accumulates at the postsynaptic density and causes proteolysis of the cell adhesion protein Ncadherin, loss of excitatory synaptic contacts and cognitive decline. Aims and Methods To identify the molecular mechanisms through which ADAM10 is associated with synaptic dysfunction in HD, we performed a system-level study of ADAM10 interactors in the brain of HD mice. We then integrated our ADAM10 dataset with the HTT interactome curated in HDinHD database (www.hdinhd.org), to look for common protein partners. Results We found that ADAM10 and HTT share presynaptic proteins as putative interactors, including Bassoon, Piccolo, ERC2 and liprin-alpha3. We therefore speculated that ADAM10 may be involved in the organization of synaptic vesicle (SV) pools, and that this function is affected in HD. Here we show that, in the cortex, active ADAM10 forms a complex with Piccolo, a key player in the recycling and maintenance of SVs. Though the level of active ADAM10 increases in the HD cortical presynaptic fraction, we observed reduced ADAM10/Piccolo immunoprecipitation. We also found that SVs density is reduced in HD cortical neurons and depleted SVs stores are restricted to presynaptic regions actively engaged in SVs release and recycling. Notably, restoring ADAM10 activity to control level in the brain of HD mice restored the ADAM10/Piccolo complex and replenished SVs in HD cortical neurons. Conclusions We conclude that increased level of active ADAM10 in HD affects the cortical presynaptic terminal through the reduction of SVs pools involved in recycling and release. The results indicate that presynaptic ADAM10 is a relevant component of HD synaptic dysfunction and reinforces the role of the cortex and the presynaptic compartment in HD.