ADAM10 (dys)function at the Huntington’s Disease cortico-striatal synapse

Huntington’s Disease (HD) is caused by a CAG repeat expansion in the Exon1 of the Huntingtin (HTT) gene. The striatum is the most vulnerable region, but prominent pathological alterations are visible also in the cortex. Indeed, multiple lines of evidence point to cortical dysfunctions and impaired cortico-striatal connection as early events in HD. As a result, presynaptic cortical dysfunction represents a very attractive site of action for developing new therapeutic approaches.

Recent studies from our group have demonstrated that a novel HTT interactor, A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), is implicated in HD synaptic dysfunction. Indeed, wild-type HTT regulates glutamatergic synapse remodeling by binding to ADAM10 and inhibiting its proteolytic activity on N-Cadherin (N-CAD). Mutant HTT binds less to active ADAM10, which accumulates at the synapse weakening synaptic communication via excessive N-CAD proteolysis leading to cognitive decline in HD mice. Intriguingly, inhibiting ADAM10 rescues N-CAD proteolysis and prevents synaptic and cognitive defects (Vezzoli et al., 2019).

Recently, we revealed that ADAM10’s interactome shares presynaptic binding partners with HTT, including vesicle transport/release regulators. These findings suggested an unexpected role of ADAM10 in orchestrating vesicle transport/release at the presynaptic district. We discovered that the level of active ADAM10 increases in the HD cortex’s presynaptic fractions, resulting in reduced synaptic vesicles. Notably, synaptic vesicle storage was restored by normalizing ADAM10 activity (Cozzolino et al., 2021).

Based on this novel role of ADAM10 at the presynapse, we propose that cortico-striatal circuitry defects, and striatal pathology, could mostly depend on mutant HTT detrimental impact on presynaptic ADAM10 in cortical afferents. To this aim, we reconstructed the cortico-striatal circuitry on-a-chip exploiting a microfluidic-based platform that allows to inhibit ADAM10 separately in the pre- (cortical) and post-synaptic (striatal) compartments. The ADAM10 inhibitor GI254023X was administered to cortical and striatal neurons independently, and cortico-striatal functionality was assessed.