Filopodia Formation Driven by Membrane Glycoprotein M6a Depends upon the Interaction of Its Transmembrane Domains

FORMOSO, K; GARCÍA, MICAELA DIANA; FRASCH, AC.; CAMILA SCORTICATI

JOURNAL OF NEUROCHEMISTRY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2015

0022-3042

Membrane glycoprotein M6a belongs to the tetraspan proteolipid protein (PLP) family. M6a has been found to promote structural plasticity in neurons and cell lines by unknown mechanisms. Its expression is decreased in the hippocampus of chronically stressed animals subjected to either psychosocial or physical stressors. It has been recently shown that Gpm6a-null mice under stress develop a claustrophobia-like phenotype. In humans, de novo duplication of GPM6A results in learning/behavioral abnormalities, and two single nucleotide polymorphisms (SNPs) in the non-coding region are linked to mood disorders. Here, we studied the dimerization state of M6a in neuronal membranes and its functional relevance. We showed that the self-interaction of the transmembrane domains (TMDs) of M6a might be driving M6a dimerization, which, in turn, is required to induce filopodia formation. Glycine mutants located in TMD2 and TMD4 of M6a affected its dimerization and therefore prevented M6a-induced filopodia formation in neurons. In silico analysis of three non-synonymous-SNPs located in the coding region of the TMDs suggested that these mutations induce protein instability. Indeed, these SNPs prevented M6a from being functional in neurons owing to decreased stability, dimerization or improper folding. Interestingly, the SNP3 (W141R), which caused endoplasmic reticulum retention, is equivalent to the one mutated in PLP1 (W161L) causing demyelinating Pelizaeus Merzbacher disease.