Altered Expression Profile of IgLON Family of Neural Cell Adhesion Molecules in the Dorsolateral Prefrontal Cortex of Schizophrenic Patients

Abstract

Neural adhesion proteins are crucial in the development and maintenance of functional neural connectivity. Growing evidence suggests that the IgLON family of neural adhesion molecules LSAMP, NTM, NEGR1, and OPCML are important candidates in forming the susceptibility to schizophrenia (SCZ). IgLON proteins have been shown to be involved in neurite outgrowth, synaptic plasticity and neuronal connectivity, all of which have been shown to be altered in the brains of patients with the diagnosis of schizophrenia. Here we optimized custom 5′-isoform-specific TaqMan gene-expression analysis for the transcripts of human IgLON genes to study the expression of IgLONs in the dorsolateral prefrontal cortex (DLPFC) of schizophrenic patients (n = 36) and control subjects (n = 36). Uniform 5′-region and a single promoter was confirmed for the human NEGR1 gene by in silico analysis. IgLON5, a recently described family member, was also included in the study. We detected significantly elevated levels of the NEGR1 transcript (1.33-fold increase) and the NTM 1b isoform transcript (1.47-fold increase) in the DLPFC of schizophrenia patients compared to healthy controls. Consequent protein analysis performed in male subjects confirmed the increase in NEGR1 protein content both in patients with the paranoid subtype and in patients with other subtypes. In-group analysis of patients revealed that lower expression of certain IgLON transcripts, mostly LSAMP 1a and 1b, could be related with concurrent depressive endophenotype in schizophrenic patients. Additionally, our study cohort provides further evidence that cannabis use may be a relevant risk factor associated with suicidal behaviors in psychotic patients. In conclusion, we provide clinical evidence of increased expression levels of particular IgLON family members in the DLPFC of schizophrenic patients. We propose that alterations in the expression profile of IgLON neural adhesion molecules are associated with brain circuit disorganization in neuropsychiatric disorders, such as schizophrenia. In the light of previously published data, we suggest that increased level of NEGR1 in the frontal cortex may serve as molecular marker for a wider spectrum of psychiatric conditions.

From Bound Cells Comes a Sound Mind: The Role of Neuronal Growth Regulator 1 in Psychiatric Disorders

“…Thus, Negr1-deficiency led to impaired cortical development resulting in the ASD phenotype. Moreover, a clinical study with schizophrenic patients showed increased expression levels of Negr1 transcript in the dorsolateral prefrontal cortex of these patients [71]. Taken together, these studies strongly support that the altered expression of Negr1 may be associated with abnormal behaviors of various psychiatric disorders (Table 1).…”

“…In addition to MDD, Negr1 has been implicated in other psychiatric disorders and neurological diseases. Several studies have provided evidence that Negr1 is involved in Alzheimer disease (AD) [69,70], autism spectrum disorder (ASD) [27], and schizophrenia (SCZ) [71]. A GWAS study using patients with comorbid MDD and AD identified negr1 as a genetic risk factor that affects AD development [70].…”

“…-Significant correlation of Negr1 mRNA expression level with both amyloid-β (Aβ) and tau (Tau) burden in AD mouse model. Karis et al 2018 [71] Schizophrenia (SCZ) Human -Increased Negr1 transcript level in dorsolateral prefrontal cortex in SCZ patient. Noh et al 2019 [60] Major depressive disorder (MDD) negr1 -/mouse -Increased anxiety-and depressive-like behavior.…”

Detecting Local Genetic Correlations with Scan Statistics

“…It was suggested that haploinsufficiency of NTM may influence brain structural volumes and increase the risk for ASD 66,67 . Alterations of NTM expression in the dorsolateral prefrontal cortex was also observed in SCZ patients 68 . Of note, SNX19 at the same locus has been prioritized as a candidate causal gene for SCZ in transcriptomic Mendelian randomization studies 69 .…”

Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks

“…Indeed, OPCML has been previously implicated in the development of schizophrenia by multiple studies in European [56] and Thai [57] populations. In addition, increased levels of an NTM isoform have recently been detected in the dorsolateral prefrontal cortex of schizophrenia patients [58]. More importantly, the concordance of putative enhancers in both schizophrenia-associated loci with genes across the entire GRB (Fig.…”