Presynaptic proteins in the orbitofrontal cortex predict Alcohol Use Disorder

ABSTRACT: Alcohol use disorder (AUD) is a life-threatening disease characterized by compulsive drinking, cognitive deficits, and social impairment that continue despite negative consequences, which are driven by dysfunction of cortical areas, such as the orbitofrontal cortex (OFC), that normally balances decisions related to reward and risk. In this study, proteomics and machine learning analysis of post-mortem OFC brain samples collected from individuals with AUD revealed dysregulation of presynaptic (e.g., AP2A1) and mitochondrial proteins that predicted the occurrence and severity of AUD. Alcohol-sensitive OFC proteins also mapped to abnormal social behaviors and interactions. Validation using reverse genetics, we found that prefrontal Ap2a1 regulates alcohol drinking in genetically diverse mouse strains. Furthermore, we demonstrated sexual dimorphism in human OFC proteins that regulate extracellular matrix structure and signaling. Together, these findings highlight the impact of excessive alcohol consumption on the human OFC proteome and identify important cross-species cortical mechanisms underlying AUD.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Phillip Wilmarth  

LAB HEAD: Patrick J. Mulholland, PhD

PROVIDER: PXD041727 | Pride | 2023-10-09

REPOSITORIES: Pride