IGLON5, THE CELL-ADHESION MOLECULE IMPLICATED IN ANTI-IGLON5 AUTOIMMUNE TAUOPATHY, INTERACTS WITH NEUROLIGIN-1 TO LIMIT EXCITATORY SYNAPSE FORMATION

IgLON5 is a poorly characterized cell-adhesion molecule (CAM) implicated in anti-IgLON5 disease, an atypical autoimmune tauopathy defined by autoantibodies against IgLON5 (anti-IgLON5 IgGs). Clinically, patients develop a progressive sleep disorder with bulbar dysfunction and cognitive impairment. Our main goal was to define the neuronal function of IgLON5.
We performed biochemical fractionation of brain tissue and found IgLON5 in synaptosomes and in the presynaptic fraction. Immunocytochemistry confirmed this localization, prompting investigation of its synaptic function.
Using gain- and loss-of-function approaches in rodent neuronal cultures, we found that IgLON5 inhibits the formation of excitatory synapses. To explore the underlying mechanism, we tested whether IgLON5 modulates synaptogenic CAMs using the synaptogenic co-culture assay. IgLON5 selectively inhibited the synaptogenic function of Neuroligin-1 (NLGN1), a postsynaptic CAM, without affecting other synaptogenic proteins. Cell-surface binding assays and co-immunoprecipitation confirmed an interaction between IgLON5 and NLGN1. Consistently, co-expression of IgLON5 and NLGN1 reduced the binding of Neurexin2α (NRNX2α), a presynaptic partner of NLGN1, to NLGN1, suggesting that IgLON5 limits excitatory synapse formation by interfering with the NLGN–NRXN complex. Ongoing in vivo studies aim to further define the role of IgLON5 as a regulator of excitatory synapses development and function.
Given evidence that excitatory synaptic contacts and neuronal activity promote Tau propagation, we propose that IgLON5 physiologically fine-tunes excitatory synaptic adhesion by restraining NLGN1 interactions. In the presence of pathological anti-IgLON5 IgGs, IgLON5 is removed from the neuronal surface, releasing this inhibitory effect, increasing excitatory synapse contacts, and exacerbating Tau pathology. We are currently testing this hypothesis.