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This glycoprotein is encoded by<jats:italic>Gpm6a<\/jats:italic>, a stress\u2010regulated gene. The hippocampus of animals chronically stressed by either psychosocial or physical stressors shows decreased M6a expression. Stressed<jats:italic>Gpm6a<\/jats:italic>\u2010null mice develop a claustrophobia\u2010like phenotype. In humans,<jats:italic>de novo<\/jats:italic>duplication of<jats:italic><jats:styled-content style=\"fixed-case\">GPM<\/jats:styled-content>6A<\/jats:italic>results in learning\/behavioral abnormalities, and two single\u2010nucleotide polymorphisms (<jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>s) in the non\u2010coding region are linked to mood disorders. Here, we studied M6a dimerization in neuronal membranes and its functional relevance. We showed that the self\u2010interaction of M6a transmembrane domains (<jats:styled-content style=\"fixed-case\">TMD<\/jats:styled-content>s) might be driving M6a dimerization, which is required to induce filopodia formation. Glycine mutants located in<jats:styled-content style=\"fixed-case\">TMD<\/jats:styled-content>2 and<jats:styled-content style=\"fixed-case\">TMD<\/jats:styled-content>4 of M6a affected its dimerization, thus preventing M6a\u2010induced filopodia formation in neurons.<jats:italic>In silico<\/jats:italic>analysis of three non\u2010synonymous<jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>s located in the coding region of<jats:styled-content style=\"fixed-case\">TMD<\/jats:styled-content>s suggested that these mutations induce protein instability. Indeed, these<jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>s prevented M6a from being functional in neurons, owing to decreased stability, dimerization or improper folding. Interestingly,<jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>3 (W141R), which caused endoplasmic reticulum retention, is equivalent to that mutated in<jats:italic><jats:styled-content style=\"fixed-case\">PLP<\/jats:styled-content>1<\/jats:italic>, W161L, which causes demyelinating Pelizaeus\u2013Merzbacher disease.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13153-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><jats:p>In this work we analyzed the functional contribution of transmembrane domains (TMDs) of the neuronal membrane glycoprotein M6a. We determined that certain glycines present in TMD2 and TMD4 are critical for filopodia induction in neurons. In addition, three nsSNPs located in the coding region of TMD2 and TMD3 of GPM6A impair M6a function by affecting its stability, folding and dimer formation.<\/jats:p>","DOI":"10.1111\/jnc.13153","type":"journal-article","created":{"date-parts":[[2015,5,5]],"date-time":"2015-05-05T06:42:51Z","timestamp":1430808171000},"page":"499-512","source":"Crossref","is-referenced-by-count":27,"title":["Filopodia formation driven by membrane glycoprotein M6a depends on the interaction of its transmembrane domains"],"prefix":"10.1111","volume":"134","author":[{"given":"Karina","family":"Formoso","sequence":"first","affiliation":[{"name":"Instituto de Investigaciones Biotecnol\u00f3gicas\u2010Instituto Tecnol\u00f3gico de Chascom\u00fas (IIB\u2013INTECH) Universidad Nacional de San Mart\u00edn (UNSAM) Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET) San Mart\u00edn Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micaela D.","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biotecnol\u00f3gicas\u2010Instituto Tecnol\u00f3gico de Chascom\u00fas (IIB\u2013INTECH) Universidad Nacional de San Mart\u00edn (UNSAM) Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET) San Mart\u00edn Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto C.","family":"Frasch","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biotecnol\u00f3gicas\u2010Instituto Tecnol\u00f3gico de Chascom\u00fas (IIB\u2013INTECH) Universidad Nacional de San Mart\u00edn (UNSAM) Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET) San Mart\u00edn Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Scorticati","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biotecnol\u00f3gicas\u2010Instituto Tecnol\u00f3gico de Chascom\u00fas (IIB\u2013INTECH) Universidad Nacional de San Mart\u00edn (UNSAM) Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET) San Mart\u00edn Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,6,17]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.20328"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504262102"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2005.06.036"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910873107"},{"key":"e_1_2_7_6_1","doi-asserted-by":"crossref","first-page":"436","DOI":"10.33588\/rn.3705.2003082","article-title":"Duplication of the PLP gene and the classical form of Pelizaeus\u2010Merzbacher disease","volume":"37","author":"Blanco\u2010Barca M. 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