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Unraveling the complexity of biological systems relies on the development of new approaches for spatially resolved proteoform-specific analysis of the proteome. Herein, we employ nanospray desorption electrospray ionization mass spectrometry imaging (nano-DESI MSI) for the proteoform-selective imaging of biological tissues. Nano-DESI generates multiply charged protein ions, which is advantageous for their structural characterization using tandem mass spectrometry (MS/MS) directly on the tissue. Proof-of-concept experiments demonstrate that nano-DESI MSI combined with on-tissue top-down proteomics is ideally suited for the proteoform-selective imaging of tissue sections. Using rat brain tissue as a model system, we provide the first evidence of differential proteoform expression in different regions of the brain.

Unraveling the complexity of biological systems relies on the development of new approaches for spatially resolved proteoform-specific analysis of the proteome. Top-down proteomics is a powerful tool, which has been used for the identification of thousands of proteoforms in biological samples. Herein, we present a first spatially resolved top-down proteomics analysis of biological tissues using nanospray desorption electrospray ionization mass spectrometry imaging (nano-DESI MSI). Nano-DESI generates multiply charged protein ions, which is advantageous for their structural characterization using tandem mass spectrometry (MS/MS). Proof-of-concept experiments demonstrate that the nano-DESI MSI combined with on-tissue top-down proteomics is ideally suited for the proteoform-selective imaging of thin tissue sections. Using rat brain tissue as a model system, we provide the first evidence of the differential proteoform expression in different regions of the brain.

Scope: Acquire imaging mass spectrometry (IMS) datasets of proteins on human kidney tissue with ~12μm spatial resolution. Expected Outcome: Visualize the proteins distribution localizing to physiological regions within the human kidney by generating ion images of multiply charged protein peaks.