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 involving compulsive drinking and cognitive deficits.
• The orbitofrontal cortex (OFC) plays a crucial role in decision-making and balancing reward/risk, potentially impaired in AUD.
• Understanding OFC's molecular changes is vital for AUD research.

Purpose of the Study:

• To investigate the proteomic alterations in the human OFC associated with AUD.
• To identify specific proteins and pathways dysregulated by excessive alcohol consumption.
• To explore cross-species mechanisms controlling alcohol drinking behavior.

Main Methods:

• Proteomic analysis of post-mortem OFC samples from AUD and control subjects.
• Bioinformatics and machine learning to identify differentially expressed proteins and predictive markers.
• Reverse genetics in mice to validate the role of identified proteins in alcohol consumption.

Main Results:

• Over 4,500 proteins were identified; 47 sex-specific proteins were linked to extracellular matrix and axonal structure.
• AUD cases showed differential expression of proteins involved in synaptic function, mitochondrial function, and transmembrane transport.
• Machine learning identified dysregulated presynaptic and mitochondrial proteins predicting AUD severity; Ap2a1 validated as a key protein influencing alcohol intake in mice.

Conclusions:

• Excessive alcohol consumption significantly impacts the human OFC proteome.
• Identified OFC proteins and pathways offer potential therapeutic targets for AUD.
• Cortical mechanisms regulating alcohol drinking are conserved across species, with Ap2a1 playing a significant role.