The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal Synapses
Single point mutations or variations in the expression of the gene encoding the neuronal glycoprotein M6a have been associated with psychiatric disorders such as Alzheimer’s disease, depression and schizophrenia. In cultured neurons, M6a positively contributes to neurite extension, axon guidance, fi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-09-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00296/full |
| _version_ | 1811253696889094144 |
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| author | Micaela D. Garcia Karina Formoso Gabriela I. Aparicio Alberto C. C. Frasch Camila Scorticati |
| author_facet | Micaela D. Garcia Karina Formoso Gabriela I. Aparicio Alberto C. C. Frasch Camila Scorticati |
| author_sort | Micaela D. Garcia |
| collection | DOAJ |
| description | Single point mutations or variations in the expression of the gene encoding the neuronal glycoprotein M6a have been associated with psychiatric disorders such as Alzheimer’s disease, depression and schizophrenia. In cultured neurons, M6a positively contributes to neurite extension, axon guidance, filopodia/spine outgrowth, and synapse formation. The endocytic processes of neuronal membrane proteins are linked to the differentiation, growth, signaling and plasticity of neurons. However, the roles of M6a and the precise mechanisms through which M6a internalizes and recycles back to the neuronal membrane are unknown. Here, by using a controlled in vitro assay, we showed that if 30–40% of M6a is endocytosed, the number of synapses in hippocampal neurons decreases. When re-establishing the levels of M6a at the cell surface, the number of synapses returned to normal values. M6a internalization involves clathrin-coated pits, probably by association between the adaptor protein 2 and the 251YEDI254 “tyrosine-based” motif located within the C-tail of M6a. Upon endocytosis, M6a is sorted to early endosome antigen 1- and Rab5-positive endosomes and then sorted back to the cell surface via Rab11-positive endosomes or to degradation via Rab7 and, finally LAMP-1-positive endosomes. Our results demonstrated that the levels of M6a at the cell surface modified the formation/maintenance of synapses, without altering the protein levels of synaptophysin or N-methyl-D-aspartate receptor type-1. This novel mechanism might be relevant during neuronal development, pruning and/or many of the neurological disorders in which the number of synapses is affected. |
| first_indexed | 2024-04-12T16:55:55Z |
| format | Article |
| id | doaj.art-98399851a2c642adbbe78c53426507b5 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-12T16:55:55Z |
| publishDate | 2017-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-98399851a2c642adbbe78c53426507b52022-12-22T03:24:15ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-09-011010.3389/fnmol.2017.00296291455The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal SynapsesMicaela D. Garcia0Karina Formoso1Gabriela I. Aparicio2Alberto C. C. Frasch3Camila Scorticati4Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Universidad Nacional de San Martín, Consejo Nacional de Investigaciones Científicas y TécnicasBuenos Aires, ArgentinaInstituto de Investigaciones Biomédicas, Universidad Católica ArgentinaBuenos Aires, ArgentinaInstituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Universidad Nacional de San Martín, Consejo Nacional de Investigaciones Científicas y TécnicasBuenos Aires, ArgentinaInstituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Universidad Nacional de San Martín, Consejo Nacional de Investigaciones Científicas y TécnicasBuenos Aires, ArgentinaInstituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Universidad Nacional de San Martín, Consejo Nacional de Investigaciones Científicas y TécnicasBuenos Aires, ArgentinaSingle point mutations or variations in the expression of the gene encoding the neuronal glycoprotein M6a have been associated with psychiatric disorders such as Alzheimer’s disease, depression and schizophrenia. In cultured neurons, M6a positively contributes to neurite extension, axon guidance, filopodia/spine outgrowth, and synapse formation. The endocytic processes of neuronal membrane proteins are linked to the differentiation, growth, signaling and plasticity of neurons. However, the roles of M6a and the precise mechanisms through which M6a internalizes and recycles back to the neuronal membrane are unknown. Here, by using a controlled in vitro assay, we showed that if 30–40% of M6a is endocytosed, the number of synapses in hippocampal neurons decreases. When re-establishing the levels of M6a at the cell surface, the number of synapses returned to normal values. M6a internalization involves clathrin-coated pits, probably by association between the adaptor protein 2 and the 251YEDI254 “tyrosine-based” motif located within the C-tail of M6a. Upon endocytosis, M6a is sorted to early endosome antigen 1- and Rab5-positive endosomes and then sorted back to the cell surface via Rab11-positive endosomes or to degradation via Rab7 and, finally LAMP-1-positive endosomes. Our results demonstrated that the levels of M6a at the cell surface modified the formation/maintenance of synapses, without altering the protein levels of synaptophysin or N-methyl-D-aspartate receptor type-1. This novel mechanism might be relevant during neuronal development, pruning and/or many of the neurological disorders in which the number of synapses is affected.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00296/fullPLP protein familyneuronal plasticitytrafficendosomal compartmentsRab GTPasesglycoprotein M6a |
| spellingShingle | Micaela D. Garcia Karina Formoso Gabriela I. Aparicio Alberto C. C. Frasch Camila Scorticati The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal Synapses Frontiers in Molecular Neuroscience PLP protein family neuronal plasticity traffic endosomal compartments Rab GTPases glycoprotein M6a |
| title | The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal Synapses |
| title_full | The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal Synapses |
| title_fullStr | The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal Synapses |
| title_full_unstemmed | The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal Synapses |
| title_short | The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal Synapses |
| title_sort | membrane glycoprotein m6a endocytic recycling pathway involves clathrin mediated endocytosis and affects neuronal synapses |
| topic | PLP protein family neuronal plasticity traffic endosomal compartments Rab GTPases glycoprotein M6a |
| url | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00296/full |
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