Adaptor protein complex 2 in the orbitofrontal cortex predicts alcohol use disorder.

Area of Science:

• Neuroscience
• Proteomics
• Genetics

Background:

• Alcohol use disorder (AUD) is a severe condition marked by compulsive drinking and cognitive impairment.
• The orbitofrontal cortex (OFC) plays a crucial role in decision-making and reward processing, potentially implicated in AUD.
• Understanding the molecular underpinnings of AUD in the OFC is vital for developing effective treatments.

Approach:

• Proteomic analysis of post-mortem orbitofrontal cortex samples from individuals with and without AUD.
• Bioinformatics and machine learning were used to identify differentially expressed proteins and predict AUD severity.
• Reverse genetics in mouse models validated the role of specific proteins, like AP2A1, in alcohol consumption.

Key Points:

• Over 4,500 proteins were identified, with 47 sex-specific proteins linked to extracellular matrix and axonal structure.
• Proteins differentially expressed in AUD cases were associated with synaptic function, mitochondrial activity, and transmembrane transport.
• Machine learning identified dysregulated presynaptic and mitochondrial proteins, including AP2A1, as predictors of AUD.
• Prefrontal Ap2a1 expression correlated with alcohol intake in mice, and specific alleles influenced consumption levels.

Conclusions:

• Excessive alcohol consumption significantly impacts the human OFC proteome.
• Identified OFC proteins and mechanisms offer cross-species insights into controlling alcohol drinking.
• This research highlights potential therapeutic targets for alcohol use disorder.