Abstract
Major depressive disorder (MDD) is a leading cause of disability worldwide and results tragically in the loss of almost one million lives in Western societies every year. This is due to poor understanding of the disease pathophysiology and lack of empirical medical tests for accurate diagnosis or for guiding antidepressant treatment strategies. Here, we have used shotgun proteomics in the analysis of post-mortem dorsolateral prefrontal cortex brain tissue from 24 MDD patients and 12 matched controls. Brain proteomes were pre-fractionated by gel electrophoresis and further analyzed by shotgun data-independent label-free liquid chromatography-mass spectrometry. This led to identification of distinct proteome fingerprints between MDD and control subjects. Some of these differences were validated by Western blot or selected reaction monitoring mass spectrometry. This included proteins associated with energy metabolism and synaptic function and we also found changes in the histidine triad nucleotide-binding protein 1 (HINT1), which has been implicated recently in regulation of mood and behavior. We also found differential proteome profiles in MDD with (n=11) and without (n=12) psychosis. Interestingly, the psychosis fingerprint showed a marked overlap to changes seen in the brain proteome of schizophrenia patients. These findings suggest that it may be possible to contribute to the disease understanding by distinguishing different subtypes of MDD based on distinct brain proteomic profiles.
Highlights
Major depressive disorder (MDD) is a serious psychiatric condition affecting approximately 10% of the world population with a lifetime prevalence of 17%.1 The effects of MDD are wide-ranging, including a negative impact on families, work and relationships, and has been associated with debilitating co-morbidities such as general ill health, substance abuse and anxiety disorders
There were no significant differences between MDD patients and controls with regards to gender, age, post-mortem and refrigeration interval and brain pH (Table 1)
The multiplex nature of selected reaction monitoring (SRM) allows the accurate quantification of tens of proteins in a single experimental run allowing its use in both pre-clinical and clinical trials as well as in clinical pipelines for detection of Signaling role of SNCA & SNCG
Summary
Major depressive disorder (MDD) is a serious psychiatric condition affecting approximately 10% of the world population with a lifetime prevalence of 17%.1 The effects of MDD are wide-ranging, including a negative impact on families, work and relationships, and has been associated with debilitating co-morbidities such as general ill health, substance abuse and anxiety disorders. The effects of MDD are wide-ranging, including a negative impact on families, work and relationships, and has been associated with debilitating co-morbidities such as general ill health, substance abuse and anxiety disorders. Together, these factors contribute to an enormous significant financial burden on the healthcare services.[2] In addition, MDD subjects account for 60% of suicides in the United States.[3] some molecular aspects of MDD have been identified, such as hypothalamic– pituitary–adrenal axis dysfunction,[4] effects on memory[5] and volume reduction of certain brain regions such as hippocampus[6] and prefrontal cortex,[7] the underlying pathophysiology of this disorder has only been partially elucidated. It is important to increase our understanding of the physiological factors underlying this condition before more effective medications can be developed
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