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

Abstract

Synaptic dysfunction is implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BP). We used quantitative mass-spectrometry to carry out deep and unbiased profiling of the proteome of synapses purified from the dorsolateral prefrontal cortex of 35 cases of SCZ, 35 cases of BP, and 35 controls. Compared to controls, SCZ and BP synapses showed substantial and similar proteomic alterations. Network and gene set enrichment analyses revealed 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 (e.g., upregulation of vesicle transport, downregulation of mitochondrial and ribosomal proteins) were 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 novel biological insights into molecular dysfunction at the synapse in SCZ and BP and serves as a resource for understanding the pathophysiology of these debilitating neuropsychiatric disorders.

Transcriptomics and proteomics of projection neurons in a circuit linking hippocampus with dorsolateral prefrontal cortex in human brain

“…These insights from bulk tissue data have been further translated into potential pathophysiological mechanisms of SCZ at gene 6,[9][10][11][12][13][14][15][16][17] , transcript 4,8,15 , and most recently, protein levels 18 .…”

Autophagosomes coordinate an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling

“…Recently, polymorphisms in the AKAP11 gene sequence that lead to protein truncation and loss-of-function have been strongly associated with increased risk for schizophrenia (SCZ) and bipolar disorder (BP) [19][20][21] . A deep-proteomic study comparing brain tissue samples from SCZ and BP patients with synaptosomal preparations from AKAP11-knockout mice revealed shared alterations in the abundance of protein classes that are important for brain function, including mitochondria, vesicle trafficking and tethering 22 . However, the molecular links between AKAP11 deficiency and neuronal dysfunction that leads to SCZ and BP remain unknown.…”

Molecular and micro-architectural mapping of gray matter alterations in psychosis

“…Psychosis has been associated with specific neurobiological alterations, such as neurotransmitters 9,10 , metabolism 11 , cell type 12,13 , and microstructure 14 . Studies on prevalent genetic variations linked to SCZ have consistently pointed towards synaptic function as key factor in terms of disease risk 15 . Specifically, dysregulation of dopaminergic neurotransmission has been detected in SCZ 16 , and several neurochemical systems have been suggested to contribute to psychosis pathophysiology, including the glutamate, gamma-aminobutyric acid (GABA), serotonin, and acetylcholine neurotransmitters 9,17 .…”