Advancement in human neuroimaging based on proximity ligation assay in brain disease

In this article we highlights the use of in situ proximity ligation assay (PLA) method to study protein-protein interactions in brain diseases. PLA enables high-sensitivity detection of protein complexes, such as G protein-coupled receptor (GPCR) heterocomplexes, in post-mortem human brains. This approach has facilitated the visualization of A2AR-D2R heterocomplexes in the striatum and contributed to understanding neuropsychiatric and neurodegenerative disorders. PLA has been instrumental in identifying pathological protein interactions in Alzheimer’s disease (AD) and Parkinson’s disease (PD). For AD, it revealed tau-ubiquitin interactions, providing insights into tau pathology. In PD, PLA demonstrated alpha-synuclein (AS) oligomers and their interactions with dopamine transporters and synapsin-III, shedding light on neurodegenerative mechanisms. It also detected AS oligomers in multiple system atrophy (MSA), offering new perspectives on disease pathology. Despite challenges such as antibody variability and post-mortem tissue degradation, PLA has significantly enhanced molecular imaging, enabling early detection of protein aggregation. This method provides a powerful tool for studying brain disorders, improving molecular understanding, and identifying potential therapeutic targets.