This study constructs a high-resolution proteomic atlas across 13 brain regions from eight donors, proposing a three-module functional framework and revealing the potential role of the midline regulatory axis in neurodevelopment and higher cognition, providing a valuable resource for investigating mechanisms of brain disorders.
Literature Overview
The study, 'Region-resolved proteomic map of the human brain: functional interconnections and neurological implications,' published in Signal Transduction and Targeted Therapy, reviews and summarizes deep proteomic analyses of 13 brain regions from eight human donors, systematically revealing region-specific protein expression patterns and their roles in brain functional organization. Using mass spectrometry, the study identified over 4,600 proteins, constructing a region-resolved brain proteomic atlas and proposing a three-module functional framework: the 'cortical integration module,' 'limbic relay network,' and 'midline regulatory axis.' The findings indicate that traditionally non-cognitive regions such as the brainstem and cerebellum also contribute to higher-order functions, while midline structures play critical roles in synaptic function, energy metabolism, and extracellular matrix homeostasis. This work provides a new molecular perspective for understanding brain functional organization and mechanisms of neurological diseases.Background Knowledge
Brain function relies on precise coordination among different regions, with its molecular basis determined by gene and protein expression profiles specific to each region. Although transcriptomic studies have revealed numerous regionally differentially expressed genes, mRNA levels often poorly reflect protein abundance, especially in the nervous system, where weak transcript-protein correlations result from factors such as protein half-life, translational regulation, and post-translational modifications. Therefore, direct proteomic analysis is essential for understanding brain function. Recent advances in spatial proteomics have enabled the resolution of region-specific protein networks, metabolic pathways, and structural modules, but most studies have been limited to single donors or animal models, limiting generalizability. Traditionally, the brainstem and cerebellum are considered primarily responsible for basic life support and motor coordination, with higher cognitive functions mediated by the cerebral cortex. However, increasing imaging and functional evidence shows these regions also participate in emotion, cognition, and behavioral regulation. This study overcomes previous limitations by conducting systematic proteomic analysis across multiple donors and brain regions, providing the most comprehensive human brain proteomic atlas to date, offering a key resource for uncovering principles of brain functional organization and disease mechanisms.
Research Methods and Experiments
The study analyzed samples from 13 brain regions of eight human donors, including four cerebral cortical lobes (frontal, temporal, parietal, occipital), subcortical structures (amygdala, hippocampus, thalamus/hypothalamus), and midline structures (corpus callosum, ventricles, optic chiasm, brainstem, cerebellum, olfactory bulb/tract). All samples underwent liquid chromatography-tandem mass spectrometry (LC-MS/MS) for proteomic quantification, identifying a total of 4,660 proteins. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and hierarchical clustering were used to assess sample separation and regional correlations. Highly expressed proteins were categorized into quartiles and subjected to functional enrichment and protein-protein interaction network analysis using GO, KEGG, and STRING databases. A brain region–protein–function association network was further constructed to systematically analyze biological processes and behavioral regulatory potential in each region.Key Conclusions and Perspectives
Research Significance and Prospects
This study provides, for the first time at the proteomic level, a systematic molecular characterization of human brain regions, revealing modular principles of brain functional organization, particularly the potential central role of midline structures in neural regulation. These findings offer a new molecular framework for understanding normal brain function and the mechanisms of neuropsychiatric disorders. Future studies could integrate single-cell proteomics, spatial transcriptomics, and functional imaging data to further resolve cell-type-specific networks.
The results suggest that neurological disorders such as Alzheimer’s disease, schizophrenia, and autism may involve coordinated dysfunctions across multiple brain regions rather than isolated lesions. Specifically, homeostatic imbalance in the midline regulatory axis may affect global brain connectivity and information integration, pointing to new therapeutic targets. Additionally, this proteomic atlas can serve as a reference resource for validating molecular similarities in animal disease models, enhancing the reliability of translational research.
Conclusion
Through systematic proteomic analysis, this study constructs a high-resolution molecular atlas of human brain regions, revealing a three-module framework for brain functional organization and highlighting the critical roles of midline structures in neurodevelopment, metabolic homeostasis, and higher cognition. The findings demonstrate that traditionally 'lower-level' regions such as the brainstem and cerebellum are extensively involved in sensory integration and behavioral regulation, challenging classical neuroanatomical concepts. The shared synaptic regulatory protein network across the four cortical lobes provides a molecular basis for understanding cognitive function, with its dysregulation potentially driving various neuropsychiatric disorders. This work not only provides a valuable resource database but also lays a solid foundation for future investigations into brain disease mechanisms and therapeutic target discovery. By integrating multi-omics data, it may be possible to further uncover the dynamic regulatory mechanisms of brain region interconnectivity, advancing the development of precision neuroscience.
