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

Sameer Aryal; Kevin Bonanno; Bryan Song; D R Mani; Hasmik Keshishian; Steven A Carr; Morgan Sheng; Borislav Dejanovic

doi:10.1016/j.celrep.2023.112497

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

Cell Rep. 2023 May 30;42(5):112497. doi: 10.1016/j.celrep.2023.112497. Epub 2023 May 11.

Authors

Sameer Aryal¹, Kevin Bonanno², Bryan Song¹, D R Mani², Hasmik Keshishian², Steven A Carr², Morgan Sheng³, Borislav Dejanovic⁴

Affiliations

¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² The Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: msheng@broadinstitute.org.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: bdejanov@broadinstitute.org.

PMID: 37171958
DOI: 10.1016/j.celrep.2023.112497

Abstract

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.

Keywords: AKAP11; CP: Neuroscience; bipolar disorder; network analysis; proteomics; schizophrenia; synapse proteome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bipolar Disorder* / genetics
Bipolar Disorder* / metabolism
Disease Models, Animal
Mice
Proteomics / methods
Schizophrenia* / genetics
Schizophrenia* / metabolism
Synapses / metabolism