Distinct proteomic profiles in post-mortem pituitary glands from bipolar disorder and major depressive disorder patients
Introduction
Bipolar disorder (BD) and major depressive disorder (MDD) have a lifetime prevalence of 20% (Hirschfeld, 2012). Individuals with either of these disorders have decreased life expectancies due to suicide and increased comorbidities such as obesity, diabetes, dyslipidemia and cardiac disease (Ferrari et al., 2013, Hauser et al., 2013). Some of these co-morbidities can be side effects from psychiatric medications (Gazalle et al., 2007, McLaren and Marangell, 2004). Also, misdiagnosis or inappropriate treatment can have negative effects on health and result in a worse outcome for patients (Bowden, 2010). Recent studies have attempted to increase our understanding of the underlying pathophysiologies of BD and MDD through identification of disease-specific biomarkers (Alsaif et al., 2013, Schneider and Prvulovic, 2013). These studies have identified hypothalamic–pituitary–adrenal (HPA) axis perturbations in many patients with mood disorders (Banki et al., 1987, Grunze, 2011, Tsigos and Chrousos, 2002). The HPA axis is a component of the diffuse neuroendocrine system involved in regulation of vital homoeostatic systems throughout the body, including blood pressure, metabolism, inflammation and fluid balance. Effects on all of these processes have been implicated in BD and MDD. In addition, pituitary size is known to be enlarged in adolescents with BD and MDD, indicating that hormonal abnormalities may occur at early stages of disease (MacMaster et al., 2008). One of the most studied components of the HPA axis is regulation of the stress response via proteolytic conversion of pro-opiomelanocortin (POMC) to adrenocorticotropin (ACTH) in the anterior pituitary (Arlt and Stewart, 2005). Secretion of ACTH into the peripheral circulation stimulates release of cortisol from the adrenal cortex, which in turn can affect brain function (Frodl and O'Keane, 2013). Under normal circumstances, cortisol also acts on the hypothalamus and pituitary in a negative feedback loop to suppress production of ACTH.
Several other proteins produced by the pituitary have effects on the brain. For example, galanin regulates cognition, neuronal growth and neuronal protection (Mechenthaler, 2008). Growth hormone (somatotropin) has been implicated in several pathways including the sleep–wake cycle, brain development and neuronal repair (Arce et al., 2013). Prolactin is involved in diverse processes such as regulation of the immune response, neurogenesis and neuronal differentiation (Larsen and Grattan, 2012). Also, the production of prolactin is tightly regulated with that of neurotransmitters such as dopamine which can affect behaviour and mood (van den Pol, 2010). The pituitary also contains prohormone-converting enzymes such as carboxypeptidase E (CPE) and prolyl-oligopeptidase 1 (POP), which are involved in proteolytic maturation of pituitary hormones and other proproteins, leading to generation of a spectrum of bioactive peptides (Hook et al., 2009, Yoshimoto et al., 1981).
The aim of this study was to identify HPA axis biomarker candidates for BD and MDD using post-mortem pituitary tissue. Protein extracts were analysed using a combination of liquid chromatography mass spectrometry (LC–MSE), selective reaction-monitoring (SRM) mass spectrometry and an enzyme assay to identify BD- and MDD-associated proteomic fingerprints. The analyses focussed on identification of secreted pituitary proteins as these could be translated into blood-based assays for future clinical studies.
Section snippets
Samples
Whole post-mortem pituitaries from 15 control, 13 BD and 14 MDD subjects were provided by the Stanley Medical Research Institute (Bethesda, MD, USA). These were matched for variables including age at death, gender, post-mortem brain interval (PMI), duration of storage, onset age, duration of illness, death by suicide and history of substance abuse (Table 1). The control subjects had no history of psychiatric or neurological disorders. Tissue had been collected post-mortem with informed consent
LC–MSE profiling
Demographic variables that were significantly different between the groups were duration of storage and illness, age of onset and death by suicide (Table 1). LC–MSE analysis of soluble and insoluble pituitary extracts from control, BD and MDD subjects resulted in identification of 796 (Supplementary Table 1) and 863 (Supplementary Table 2) proteins, respectively (Supplementary Fig. 1). This translated to 1224 unique identifications with 435 proteins overlapping between the two fractions. All
Discussion
This is the first LC–MSE profiling analysis of post-mortem pituitary tissues comparing two major psychiatric disorders. The analysis revealed differences in proteins and molecular pathways between BD and MDD patients. BD patients showed significantly increased levels of the hormones POMC and galanin. The additional finding that the levels of these hormones were significantly correlated is consistent with reports that galanin stimulates activity of the POMC-derived peptide ACTH (Malendowicz
Ethical approval statement
All subjects gave informed written consent. Clinical investigations were conducted according to the Declaration of Helsinki, and the University of Cambridge ethical committee approved the study.
Role of funding source
This work was supported by the Stanley Medical Research Institute (SMRI) (07R-1888), the Dutch Fund for Economic Structure Reinforcement (FES), under grant agreement number 0908 (NeuroBasic PharmaPhenomics project) and the European Union FP7 SchizDX research programme (grant reference 223427). The funding sources had no further role in: the study design; in the collection, analysis and interpretation of the data; in the report writing; and in the decision to submit the paper for publication.
Author's contributions
V. Stelzhammer and M. Alsaif analysed the samples and wrote the Manuscript. H. Steeb analysed the samples. H. Rahmoune, P.C. Guest and S. Bahn designed the study and edited the manuscript. Man K. Chan analysed the data and edited the manuscript. All authors reviewed and approved the article.
Statement of interest
Sabine Bahn has consulted for Myriad Genetics Inc. This does not interfere with the policies of the journal regarding sharing or ownership of data and materials. All other authors do not report any conflicts of interest. Appropriate approval and procedures were used concerning subjects.
Acknowledgements
This research was supported by the Stanley Medical Research Institute (SMRI), the European Union FP7 SchizDX research programme (grant reference 223427) and the NeuroBasic grant from the Dutch government. We also thank Dr. Jason D. Cooper for his statistical advice, the SMRI for the generous donation of post-mortem pituitaries and Maree Webster for useful discussion.
References (53)
- et al.
Role of growth hormone (GH) in the treatment on neural diseases: from neuroprotection to neural repair
Neurosci Res
(2013) - et al.
Adrenal corticosteroid biosynthesis, metabolism, and action
Endocrinol Metab Clin North Am
(2005) - et al.
Pro-opiomelanocortin-related peptides in cerebrospinal fluid: a study of manic-depressive disorder
Psychiatry Res
(1985) Proopiomelanocortin-derived peptides
Endocrinol Metab Clin North Am
(1994)- et al.
Hypothalamic-pituitary-adrenal axis and bipolar disorder
Psychiatr Clin North Am
(2005) - et al.
How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans
Neurobiol Dis
(2013) - et al.
Mechanisms of action of the antidepressants fluoxetine and the substance P antagonist L-000760735 are associated with altered neurofilaments and synaptic remodeling
Brain Res
(2004) - et al.
Altered levels of circulating insulin and other neuroendocrine hormones associated with the onset of schizophrenia
Psychoneuroendocrinology
(2011) - et al.
Analysis of the trypanosome flagellar proteome using a combined electron transfer/collisionally activated dissociation strategy
J Am Soc Mass Spectrom
(2009) - et al.
Galanin enhances and a galanin antagonist attenuates depression-like behaviour in the rat
Eur Neuropsychopharmacol
(2007)