Deep proteomics identifies shared molecular pathway alterations in synapses of patients with schizophrenia and bipolar disorder and mouse model

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. [Display omitted] •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 Aryal et al. find substantial and similar alterations in proteins and molecular pathways in the synaptic proteome of humans with schizophrenia (SCZ) and bipolar disorder (BP). They also find some of the same pathway changes in synapses purified from Akap11 mutant mice, a genetic model for both disorders.