TY - JOUR
T1 - Top-Down Proteomics Enables Comparative Analysis of Brain Proteoforms between Mouse Strains
AU - Davis, Roderick G.
AU - Park, Hae Min
AU - Kim, Kyunggon
AU - Greer, Joseph B.
AU - Fellers, Ryan T.
AU - Leduc, Richard D.
AU - Romanova, Elena V.
AU - Rubakhin, Stanislav S.
AU - Zombeck, Jonathan A.
AU - Wu, Cong
AU - Yau, Peter M.
AU - Gao, Peng
AU - Van Nispen, Alexandra J.
AU - Patrie, Steven M.
AU - Thomas, Paul M.
AU - Sweedler, Jonathan V.
AU - Rhodes, Justin S.
AU - Kelleher, Neil L.
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/3/20
Y1 - 2018/3/20
N2 - Over the past decade, advances in mass spectrometry-based proteomics have accelerated brain proteome research aimed at studying the expression, dynamic modification, interaction and function of proteins in the nervous system that are associated with physiological and behavioral processes. With the latest hardware and software improvements in top-down mass spectrometry, the technology has expanded from mere protein profiling to high-throughput identification and quantification of intact proteoforms. Murine systems are broadly used as models to study human diseases. Neuroscientists specifically study the mouse brain from inbred strains to help understand how strain-specific genotype and phenotype affect development, functioning, and disease progression. This work describes the first application of label-free quantitative top-down proteomics to the analysis of the mouse brain proteome. Operating in discovery mode, we determined physiochemical differences in brain tissue from four healthy inbred strains, C57BL/6J, DBA/2J, FVB/NJ, and BALB/cByJ, after probing their intact proteome in the 3.5-30 kDa mass range. We also disseminate these findings using a new tool for top-down proteomics, TDViewer and cataloged them in a newly established Mouse Brain Proteoform Atlas. The analysis of brain tissues from the four strains identified 131 gene products leading to the full characterization of 343 of the 593 proteoforms identified. Within the results, singly and doubly phosphorylated ARPP-21 proteoforms, known to inhibit calmodulin, were differentially expressed across the four strains. Gene ontology (GO) analysis for detected differentially expressed proteoforms also helps to illuminate the similarities and dissimilarities in phenotypes among these inbred strains.
AB - Over the past decade, advances in mass spectrometry-based proteomics have accelerated brain proteome research aimed at studying the expression, dynamic modification, interaction and function of proteins in the nervous system that are associated with physiological and behavioral processes. With the latest hardware and software improvements in top-down mass spectrometry, the technology has expanded from mere protein profiling to high-throughput identification and quantification of intact proteoforms. Murine systems are broadly used as models to study human diseases. Neuroscientists specifically study the mouse brain from inbred strains to help understand how strain-specific genotype and phenotype affect development, functioning, and disease progression. This work describes the first application of label-free quantitative top-down proteomics to the analysis of the mouse brain proteome. Operating in discovery mode, we determined physiochemical differences in brain tissue from four healthy inbred strains, C57BL/6J, DBA/2J, FVB/NJ, and BALB/cByJ, after probing their intact proteome in the 3.5-30 kDa mass range. We also disseminate these findings using a new tool for top-down proteomics, TDViewer and cataloged them in a newly established Mouse Brain Proteoform Atlas. The analysis of brain tissues from the four strains identified 131 gene products leading to the full characterization of 343 of the 593 proteoforms identified. Within the results, singly and doubly phosphorylated ARPP-21 proteoforms, known to inhibit calmodulin, were differentially expressed across the four strains. Gene ontology (GO) analysis for detected differentially expressed proteoforms also helps to illuminate the similarities and dissimilarities in phenotypes among these inbred strains.
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U2 - 10.1021/acs.analchem.7b04108
DO - 10.1021/acs.analchem.7b04108
M3 - Article
C2 - 29481055
AN - SCOPUS:85044192715
SN - 0003-2700
VL - 90
SP - 3802
EP - 3810
JO - Analytical Chemistry
JF - Analytical Chemistry
IS - 6
ER -