In the brain, cell adhesion molecules (CAMs) are critical for neurite outgrowth, axonal fasciculation, neuronal survival and migration, and synapse formation and maintenance. Among CAMs, the IgLON family comprises five members: Opioid Binding Protein/Cell Adhesion Molecule Like (OPCML or OBCAM), Limbic System Associated Membrane Protein (LSAMP), neurotrimin (NTM), Neuronal Growth Regulator 1 (NEGR1), and IgLON5. IgLONs exhibit three N-terminal C2 immunoglobulin domains; several glycosylation sites; and a glycosylphosphatidylinositol anchoring to the membrane. Interactions as homo- or heterodimers in cis and in trans, as well as binding to other molecules, appear critical for their functions. Shedding by metalloproteases generates soluble factors interacting with cellular receptors and activating signal transduction. The aim of this review was to analyse the available data implicating a role for IgLONs in neuropsychiatric disorders. Starting from the identification of a pathological role for antibodies against IgLON5 in an autoimmune neurodegenerative disease with a poorly understood mechanism of action, accumulating evidence links IgLONs to neuropsychiatric disorders, albeit with still undefined mechanisms which will require future thorough investigations.

The association between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) has been extensively demonstrated, but despite this, the pathophysiological mechanisms underlying it are still unknown. In previous work, we discovered a central role for the autophagy pathway in the common alterations observed between AD and T2DM. In this study, we further investigate the role of genes belonging to this pathway, measuring their mRNA expression and protein levels in 3xTg-AD transgenic mice, an animal model of AD. Moreover, primary mouse cortical neurons derived from this model and the human H4Swe cell line were used as cellular models of insulin resistance in AD brains. Hippocampal mRNA expression showed significantly different levels for Atg16L1, Atg16L2, GabarapL1, GabarapL2, and Sqstm1 genes at different ages of 3xTg-AD mice. Significantly elevated expression of Atg16L1, Atg16L2, and GabarapL1 was also observed in H4Swe cell cultures, in the presence of insulin resistance. Gene expression analysis confirmed that Atg16L1 was significantly increased in cultures from transgenic mice when insulin resistance was induced. Taken together, these results emphasise the association of the autophagy pathway in AD-T2DM co-morbidity, providing new evidence about the pathophysiology of both diseases and their mutual interaction.

The IgLON family of cell adhesion molecules consists of five members (LSAMP, OPCML, neurotrimin, NEGR1, and IgLON5) discovered as supporters of neuronal development, axon growth and guidance, and synapse formation and maintenance. Tumour suppression properties have recently been emerging based on antiproliferative effects through the modulation of oncogenic pathways. Available evidence endorses a role for non-coding RNAs or microRNAs as relevant controllers of IgLON molecule expression that can impact their critical physiological and pathological roles. Current findings support a function for long non-coding RNAs and microRNAs in the modulation of LSAMP expression in cell senescence, cancer biogenesis, addiction, and pulmonary hypertension. For OPCML, data point to a role for several microRNAs in the control of tumorigenesis. MicroRNAs were detected in neurotrimin-mediated functions in cancer biogenesis and in Schwann cell responses to peripheral nerve injury. For NEGR1, studies have mainly investigated microRNA involvement in neuronal responses to ischaemic injury, although data also exist about tumorigenesis and endothelial cell dysfunction. For IgLON5, information is only available about microRNA involved in myocardial infarction. In conclusion, despite much information being still missing and further research needed, the emerging picture favours a model in which non-coding RNAs exert a crucial role in modulating IgLON expression, ultimately affecting their important physiological functions.

Background: Neuronal growth regulator 1 (NEGR1) is an IgLON cell adhesion molecule significantly associated with depression risk in genome-wide association studies. Since the role of NEGR1 in depression pathophysiology remains incompletely understood, we investigated changes in NEGR1-associated gene expression levels in stress-susceptible male mice exposed to chronic restraint stress. Methods: Mice were subjected to 21 consecutive days of restraint stress, and stress-induced maladaptive phenotypes were evaluated by tail suspension, forced swim, splash, and open field tests. After sacrifice, the hippocampi were collected, and the levels of NEGR1-associated genes were assessed by quantitative polymerase chain reaction (qPCR). Results: In the stress-exposed group, weight was significantly reduced, and immobility time was significantly higher in the tail suspension and the forced swim tests, while grooming bouts in the splash test were reduced. No changes were observed in the open field test. A z-score normalization integrating all behavioural parameters was applied to classify the animals as resilient or susceptible to restraint stress. In stress-susceptible mice, NEGR1, Fibroblast Growth Factor Receptor 2 (FGFR2), Limbic System-Associated Membrane Protein (LSAMP), and Neurotrimin (NTM) mRNA levels were significantly higher compared to controls, while ADAM Metallopeptidase Domain 10 (ADAM10), a metalloprotease releasing NEGR1 from neuronal membranes, was significantly reduced. Interestingly, ADAM10 expression negatively correlated with the behavioural z-score, whereas NEGR1 and LSAMP expression showed positive correlations. Conclusions: These findings indicate a potential role for NEGR1 in depressive-like behaviors elicited in a stress-susceptible phenotype. Considering NEGR1 genetic association with depression, our results suggest that the NEGR1 pathway may contribute to depression pathophysiology by modulating the interplay between genetic predisposition and exposure to stress as a crucial environmental precipitating factor.