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"Although bipolar disorder and schizophrenia are diagnosed as distinct psychiatric conditions, both are considerably heritable with molecular roots that are poorly understood. Some people diagnosed with one disorder have symptoms and clinical features in common with the other, supporting the notion that the conditions lie on a spectrum. And human genetics studies have suggested that the junctions between brain cells, known as synapses, play a key role in both conditions. ...
Their analysis revealed changes in synapse proteins that were remarkably similar in the two conditions. In mice with a mutated gene that’s been linked to both conditions, the scientists found that related biochemical pathways were similarly altered. ...
Their analysis revealed changes in synapse proteins that were remarkably similar in the two conditions. In mice with a mutated gene that’s been linked to both conditions, the scientists found that related biochemical pathways were similarly altered. ...
Synaptic surprises
Isolating and purifying synapses from brain tissue samples is no easy task, but that is what the team had to do to analyze the structure’s proteins — its working parts — at a large scale. ...
In the current study, the researchers purified synapses from postmortem tissue from an area of the brain known as the dorsolateral prefrontal cortex, from 35 individuals who had been diagnosed with schizophrenia, 35 people with bipolar disorder, and 35 unaffected individuals. Collaborators in the Proteomics Platform analyzed the purified synapses by mass spectrometry, measuring the abundance of thousands of proteins and protein fragments in an unbiased way. ...
In samples from people with each disorder, the team observed changes in the levels of hundreds of proteins compared to control individuals. Strikingly, more than 200 of these proteins were either enriched or depleted similarly in both conditions. The scientists were surprised by how comparable the patterns of protein changes were between the disorders. ..."From the highlights and abstract:
"Highlights
• Considerable and similar synapse proteome changes in SCZ and BP
• Core synaptic, mitochondrial, and ribosomal protein networks are reduced in SCZ/BP
• Increase in vesicle tethering-, trafficking- and autophagy-related protein networks
• Similar pathway changes in synapses from patients with SCZ/BP and Akap11-deficient mice
Summary
Synaptic dysfunction is implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BP). We use quantitative mass spectrometry to carry out deep, unbiased proteomic profiling of synapses purified from the dorsolateral prefrontal cortex of 35 cases of SCZ, 35 cases of BP, and 35 controls. Compared with controls, SCZ and BP synapses show substantial and similar proteomic alterations. Network analyses reveal upregulation of proteins associated with autophagy and certain vesicle transport pathways and downregulation of proteins related to synaptic, mitochondrial, and ribosomal function in the synapses of individuals with SCZ or BP. Some of the same pathways are similarly dysregulated in the synaptic proteome of mutant mice deficient in Akap11, a recently discovered shared risk gene for SCZ and BP. Our work provides biological insights into molecular dysfunction at the synapse in SCZ and BP and serves as a resource for understanding the pathophysiology of these disorders."
Graphical abstract
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