Research paperAltered plasma protein glycosylation in a mouse model of depression and in patients with major depression
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.
Section snippets
Animals
All experimental protocols were approved by the Ethics Committee for Animal Experimentation of Yamaguchi University School of Medicine. All experimental procedures were performed in accordance with the Guidelines for Animal Care and Use by the Committee of the Yamaguchi University Graduate School of Medicine.
Twenty-three male BALB/c mice (8 weeks old) were housed in groups of five or fewer in plastic cages and maintained on a 12-h light/dark schedule in a room with controlled temperature (24 °C)
Lectin microarray in plasma proteins from a mouse model of depression
We first examined whether altered plasma protein glycosylation could be observed in a mouse model of depression. We previously reported that BALB/c mice show susceptibility to a CUMS regimen consisting solely of environmental and social stressors (e.g., excluding the use of food/water deprivation and nociceptive stimuli) (Abe-Higuchi et al., 2016, Higuchi et al., 2016, Uchida et al., 2011). Additionally, increases in depression-like behaviors after CUMS exposure were prevented by treatment with
Discussion
To our knowledge, this is the first study to investigate plasma protein glycosylation status in samples obtained from CUMS mice and patients with MDD using a lectin array. ABA, TJA-I, and MAL_I binding intensities were significantly altered in CUMS mice irrespective of IMI treatment (Fig. 1), suggesting that these lectins may be markers of a stress response in depression model mice. In human samples, ten lectin binding intensities were altered in remitted patients compared to HC participants
Strengths and limitations
A strength of this study was high diagnostic accuracy, as all patients were followed from depression into remission. We also rigorously corrected lectin array data p-values using the FDR method. Additionally, we cross-matched results from patients with MDD to those from a mouse model of depression.
Yet, this study also had several limitations. First, our study samples were relatively small and thus the statistical power of our analyses may have been limited. Second, human participants included
Conclusions
In conclusion, our data uncover common glycosylation markers in plasma from depression model mice and clinical patients with MDD. Sia-alpha2-6Gal/GalNAc glycan structures were identified as potential plasma biomarkers of depression; however, the function of alpha2-6Gal/GalNAc-sialylation in the brain and particularly in MDD remains unclear and requires further investigation. Additionally, our results suggest that the expression of ST6GALNAC2 may be a useful marker of MDD in patients. Future
Role of the funding source
This study was supported in part by grants from the JSPS KAKENHI (26670542 and 16K10189 to H.Y. and 15K09832 to K.M.), the “Integrated Research on Neuropsychiatric Disorders” conducted under the Strategic Research Program for Brain Sciences from the MEXT and AMED (to H.Y.), and GSK Japan (to H.Y.).
Acknowledgments
The authors would like to thank Drs. Masato Fukuda (Gunma University) and Masahiko Mikuni (Hokkaido University) for assisting with the design of our clinical study. We also thank Dr. Masao Yamada (Glyco Technica Ltd.) for assisting with the lectin microarray analysis.
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2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Furthermore, differences in serum IL-6 and CRP levels were associated with similar N-glycome profile as observed in MDD patients and patients with more severe symptoms (Boeck et al., 2018), which indicates interplay between N-glycosylation, inflammation and pathological manifestation of depression while potentiating the role of early childhood abuse on development and clinical course of depression later in life (Nelson et al., 2017). The alternations in sialyation of (glyco)proteins in depression was also showed by Yamagata et al. (2018) who reported a higher expression of α-N-acetylgalactosaminide α − 2,6-sialytransferase 2 protein in leukocytes of depressed patients compared to remitted ones. Dysregulated sialyation (specifically decreased plasma sialyltransferase: cortisol ratio) was shown to affect HPA axis function which has been involved in development and progression of numerous psychiatric diseases, including depression (Maguire et al., 1997).