Altered plasma protein glycosylation in a mouse model of depression and in patients with major depression

Highlights

• We investigated plasma protein glycosylation in murine and human depression.

• Sia-alpha2-6Gal/GalNAc was decreased in the mouse model and in patients.

• ST6GALNAC2 expression in leukocytes may be a biological marker of depression.

Abstract

Background

Glycosylation is a common posttranslational modification in protein biosynthesis that is implicated in several disease states. It has been reported that specific protein glycan structures are useful as biomarkers for cancer and some neuropsychiatric diseases; however, the relationship between plasma protein glycosylation and major depressive disorder (MDD) has not been investigated to date. The aim of this study was to determine whether plasma protein glycan structures are altered in depression using a stress-based mouse model and samples from patients with MDD.

Methods

We used chronic ultra-mildly stressed mice that were untreated or treated with imipramine as mouse models of depression and remission, respectively. We also made comparisons between samples from depressed and remitted patients with MDD. Protein glycosylation was analyzed using a lectin microarray that included 45 lectins with binding affinities for various glycan structures.

Results

Sia-alpha2-6Gal/GalNAc was a commonly altered glycan structure in both depression model mice and patients with MDD. Moreover, the expression of ST6GALNAC2 was decreased in leukocytes from patients with MDD.

Limitations

Our study samples were small and we did not identify specific alpha2-6Gal/GalNAc-sialylated proteins.

Conclusions

The glycan structure Sia-alpha2-6GalNAc in plasma protein and ST6GALNAC2 expression in peripheral leukocytes may have utility as candidate biomarkers for the clinical diagnosis and monitoring of MDD.

Introduction

The burden of depression is increasing worldwide (World Health Organization, 2004). Early intervention in patients with depression is critical for effective treatment, as longer durations of untreated depression are associated with poorer clinical outcomes and disability (Ghio et al., 2014). The success of early intervention depends on the availability of precise and subjective differential diagnostic criteria; yet, the current operational diagnostic criteria (the International Classification of Diseases, 10th revision [ICD-10] and the Diagnostic and Statistical Manual of Mental Disorders, fifth edition [DSM-5]) rely on depression symptoms and do not include any laboratory findings such as blood test results or brain imaging findings. Thus, biological markers for depression represent a critical unmet need for objective clinical assessment.

Glycosylation is a posttranslational protein modification that regulates a number of biological processes such as cell adhesion, signal transduction, and endocytosis (Dalziel et al., 2014, Ohtsubo and Marth, 2006). Glycosylation has been also associated with several disease states, including cancer (Stowell et al., 2015) and autoimmune diseases (Willison and Goodyear, 2013). In particular, serum levels of glycoconjugates such as CA19-9 and CA125 are useful diagnostic markers for several cancers (Adamczyk et al., 2012, Almeida and Kolarich, 2016). In psychiatric studies, impaired polysialic acid structure and synthesis has been associated with schizophrenia (Barbeau et al., 1995, Isomura et al., 2011). One report demonstrated altered patterns of gamma-aminobutyric acid receptor type A subunit N-glycosylation in the superior temporal gyrus of schizophrenia patients (Mueller et al., 2013). Additionally, specific protein glycosylation patterns have been proposed as biological disease markers for Alzheimer's disease (Liang et al., 2015, Schedin-Weiss et al., 2014), attention-deficit hyperactivity disorder, and autism spectrum disorders (Pivac et al., 2011). Importantly, no study to date has reported patterns of protein glycosylation in major depressive disorder (MDD).

Lectins are carbohydrate-binding proteins that bind different glycan structures with varying specificities (Hirabayashi et al., 2013) and are thus useful for evaluating protein glycosylation. In the present study, we used a lectin microarray analysis to evaluate the glycosylation status of plasma proteins from both an ultra-mildly stressed mouse model of depression and patients with MDD. Our data suggest that glycosylation status is a useful indicator of depression in both preclinical and clinical contexts.