nsSNPs within the extracellular loops of M6a impair its neuroplastic function

ANTONELLA LEÓN; ROCÍO GUTIÉRREZ FUSTER; IGNACIO SALLABERRY; GABRIELA INÉS APARICIO; LAURA ESTRADA; CAMILA SCORTICATI

CABA

Congreso; XXXVII Congreso de la Sociedad argentina de investigacion en neurociencias; 2022

SAN

Neuronal glycoprotein M6a expression levels or polymorphisms within the GPM6A gene are associated with neuropsychiatric disorders like schizophrenia, depression and claustrophobia. M6a promotes neurite outgrowth, filopodia formation and dendritic spine and synapse maintenance in vitro. Although strong evidence suggests that the extracellular loops of M6a (ECs) are responsible for its function, the molecular mechanisms linking M6a to the onset of such diseases remain unknown. To gain knowledge on these mechanisms, we aim to characterize new non-synonymous polymorphisms (nsSNPs) within the ECs of GPM6A. We identified six nsSNPs (T71P, T76I, M154V, F156Y, R163Q and T210N) that impair M6a-induced plasticity in neuronal cultures; even though M6a´s expression, subcellular localization and folding are not affected by these nsSNPs. Previous reports showed that M6a dimerization is necessary to induce filopodia and synapse formation. M6a´s ECs are involved in homo- and heterotypic protein-protein interactions and might lead to the formation of M6a oligomers at the plasma membrane. Thus, we are currently evaluating whether the nsSNPs might disturb M6a´s oligomerization state. Our preliminary results suggest that the damaging effect of these nsSNPs could be related to a decrease in protein oligomerization. These results highlight the importance of reverse genetics approaches to gain knowledge on M6a´s mechanisms of action and genetic susceptibility of certain GPM6A variants.