CONICET | Buscador de Institutos y Recursos Humanos

Nowadays, great efforts are made to gain insight into the molecular mechanisms that underlie structural neuronal plasticity. Identifying signaling pathways involved in the development of psychiatric disorders aids the screening of possible therapeutic targets. Genetic variations or alterations in GPM6A expression are linked to neurological disorders such as schizophrenia, depression, and Alzheimer?s disease. GPM6A encodes the neuronal surface glycoprotein M6a that promotes structural plasticity by unknown mechanisms. A substantial body of evidence suggests that the extracellular loops command M6a´s function. However, the proteins that associate with them and that influence neuronal plasticity have not been determined yet. To address this question, we generated a chimera protein that only contains the extracellular loops of M6a and performed a co-immunoprecipitation with rat hippocampus samples followed by TMT/MS. Here, we report 72 novel proteins, which are candidates to interact with M6a´s extracellular loops and modify its function. Gene ontology analysis showed that 65 % of the enriched proteins belong to the category ?synapse part? at both sides of the synaptic cleft ?neuron projections? (49 %) and ?presynaptic compartment? (51 %). We showed that endogenous M6a interacts with piccolo, synaptic vesicle protein 2B and synapsin 1 in mature cultured hippocampal neurons. Interestingly, about 28 % of the proteins left were related to the ?myelin sheath? annotation, suggesting that M6a could interact with proteins at the surface of oligodendrocytes. Indeed, we demonstrated the (cis- and trans-) interaction between M6a and proteolipid protein PLP in neuroblastoma N2a cells. Finally, the 72 enriched proteins were subjected to disease-associated genes screening by DisGeNET. Apart from the diseases that have already been associated with M6a, most of the curated proteins are also involved in ?autistic disorder?, ?epilepsy?, and ?seizures? amplifying the spectrum of disorders in which M6a could play a role. Data are available via ProteomeXchange with identifier PXD017347