Next-generation brain proteomics: Integrating single-cell, spatial, and multi-omics for clinical biomarker discovery

Area of Science:

• Neuroscience
• Proteomics
• Biochemistry

Background:

• The mammalian brain's complexity relies on neurons and glia, with the dynamic proteome underpinning neural computation and disease.
• Traditional bulk tissue proteome cataloguing is evolving towards high-sensitivity single-cell and spatial resolution in neuroproteomics.

Purpose of the Study:

• To review the technological advancements in neuroproteomics, focusing on next-generation platforms.
• To examine the insights gained into proteomic remodeling driving lineage specification and synaptic plasticity.
• To discuss the clinical translation of neuroproteomic findings for precision medicine.

Main Methods:

• Integration of next-generation platforms like TIMS-PASEF and Orbitrap-Astral for deep phenotypic profiling.
• Analysis of proteomic remodeling linked to temporal protein expression waves and biological function.
• Verification of aberrant signatures in cerebrospinal fluid (CSF) and validation in plasma.

Main Results:

• Next-generation platforms provide deeper, faster profiling of limited brain samples.
• Proteomic studies reveal remodeling in lineage specification and synaptic plasticity.
• Clinical translation involves CSF and plasma validation for precision medicine.

Conclusions:

• Despite advancements, challenges in proteome coverage persist due to dynamic range and detection limits.
• Fused multi-omics integration and Artificial Intelligence (AI) are essential for decoding complex brain pathology.
• Neuroproteomics offers a powerful approach to understand neural computation, disease mechanisms, and develop precision medicine strategies.