Neuronal Glycoprotein M6a: An Emerging Molecule in Chemical Synapse Formation and Dysfunction

Abstract

The cellular and molecular mechanisms underlying neuropsychiatric and neurodevelopmental disorders show that most of them can be categorized as synaptopathies—or damage of synaptic function and plasticity. Synaptic formation and maintenance are orchestrated by protein complexes that are in turn regulated in space and time during neuronal development allowing synaptic plasticity. However, the exact mechanisms by which these processes are managed remain unknown. Large-scale genomic and proteomic projects led to the discovery of new molecules and their associated variants as disease risk factors. Neuronal glycoprotein M6a, encoded by the GPM6A gene is emerging as one of these molecules. M6a has been involved in neuron development and synapse formation and plasticity, and was also recently proposed as a gene-target in various neuropsychiatric disorders where it could also be used as a biomarker. In this review, we provide an overview of the structure and molecular mechanisms by which glycoprotein M6a participates in synapse formation and maintenance. We also review evidence collected from patients carrying mutations in the GPM6A gene; animal models, and in vitro studies that together emphasize the relevance of M6a, particularly in synapses and in neurological conditions.

Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease

“…Fig 5). These genes include neurotransmitter receptor genes (such as Gabra1, Gabra3, Gria3, Grik5, Grind2d, Npy1r); ion channels genes (such as Cacna1a, Cacna1g, Cacnb3, Clcn3); gap junction genes (Gjc1, Gjb5); transient receptor potential channel genes (Trpv4, Trpc1, Trpc6); potassium channel genes (such as Kcnn1, Kcnj8, Kcnd3, Kcnh3, Kcns3); hormone encoding genes (Ghrh, Gnrh1, Nucb2) along with other neuronal genes such as, Prss12 (encoding for Neurotrypsin) 61 , Uchl1 (encoding for pan-neuronal marker PGP9.5) 62 , Cplx2 (encoding for Complexin 2) 63 , Gpm6a (encoding for neuronal membrane glycoprotein M6-A) 64 , and Vamp2 (encoding for Synaptobrevin 2) 65 (Suppl. Fig 5).…”

Genetic Predisposition to Schizophrenia and Depressive Disorder Comorbidity

“…M6a is involved in neuron development and synapse formation and plasticity [ 62 ], and it was also recently proposed as a gene target in various neuropsychiatric disorders where it could also be used as a biomarker [ 63 ] of schizophrenia and depression disorder comorbidity.…”

“…The cellular and molecular mechanisms underlying mental disorders show that most of them can be categorized as synaptopathies or damage of synaptic function and plasticity. Synaptic formation and maintenance are orchestrated by protein complexes that are in turn regulated in space and time during neuronal development allowing synaptic plasticity [ 63 ]. In addition, neurotransmission disorder plays an important role.…”

Myelin‐associated glycoprotein alters the neuronal secretome and stimulates the release of TGFβ and proteins that affect neural plasticity

“…4A). Of the four membrane proteins, the glucosaminyltransferase MGAT1 and the anion exchange protein B3AT are not cell surface receptors, and while neuronal membrane glycoprotein M6a (GPM6a) has a role in promoting neurite outgrowth and synaptogenesis in developing neurons [36,37], its intracellular domains lack enzymatic activity [37], and it is therefore likely incapable of initiating the intracellular signals required to transactivate the TGFβ receptor. The final protein was DDR1, a classical tyrosine kinase receptor that is expressed in CGN and required for axonogenesis [38].…”