Progress in Top-Down Proteomics and the Analysis of Proteoforms

Annual Review of Analytical Chemistry

Volumn 9, Issue , 2016, Pages 499-519

  Toby, Timothy K ^a   Fornelli, Luca ^a   Kelleher, Neil L ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

Author keywords

Intact protein analysis; Mass spectrometry; Proteoforms; Top down proteomics; Translational proteomics

Indexed keywords

MASS SPECTROMETRY; MOLECULAR BIOLOGY; SPECTROMETRY;

DISSOCIATION METHODS; INTACT PROTEINS; INTRAMOLECULAR COMPLEXITY; PROTEOFORMS; PROTEOMICS; SEQUENCE MODIFICATION; TOP DOWN PROTEOMICS; TRANSLATIONAL RESEARCH;

PROTEINS;

PROTEIN;

ANIMAL; HUMAN; MASS SPECTROMETRY; PROTEOMICS;

ANIMALS; HUMANS; MASS SPECTROMETRY; PROTEINS; PROTEOMICS;

EID: 84975467064     PISSN: 19361327     EISSN: 19361335     Source Type: Book Series    
DOI: 10.1146/annurev-anchem-071015-041550     Document Type: Review

References (117)

1. Smith L, KelleherN, Consort. Top Down Proteom. 2013. Proteoform: A single term describing protein complexity. Nat. Methods 10:186-87
2. Chait B. 2006. Mass spectrometry: bottom-up or top-down? Science 314:65-66
3. Nesvizhskii A, Aebersold R. 2005. Interpretation of shotgun proteomic data: The protein inference problem. Mol. Cell. Proteom. 4:1419-40
4. Gross JH. 2004. Mass Spectrometry: A Textbook. New York: Springer
5. WaltherT,MannM. 2010. Mass spectrometry-based proteomics in cell biology. J. Cell Biol. 190:491-500
6. Scigelova M, Hornshaw M, Giannakopulos A, Makarov A. 2011. Fourier transform mass spectrometry. Mol. Cell. Proteom. 10:M111.009431
7. Zhang Y, Fonslow B, Shan B, Baek M, Yates JR 3rd. 2013. Protein analysis by shotgun/bottom-down proteomics. Chem. Rev. 113:2343-94
8. Fenn J, Mann M, Meng C, Wong S, Whitehorse C. 1989. Electrospray ionization for mass spectrometry of large biomolecules. Science 246:64-71
9. Kelleher N, Lin H, Valaskovic G, Aaserud D, Fridriksson E, McLafferty F. 1999. Top down versus bottom up protein characterization by tandem high-resolution mass spectrometry. J. Am. Chem. Soc. 121:806-12
10. Guner H, Close P, Cai W, Zhang H, Peng Y, et al. 2014. MASH suite: A user-friendly and versatile software interface for high-resolution mass spectrometry data interpretation and visualization. J. Am. Soc. Mass Spectrom. 25:464-70
11. Fellers R, Greer J, Early B, Yu X, LeDuc R, et al. 2015. ProSight Lite: graphical software to analyze top-down mass spectrometry data. Proteomics 15:1235-38
12. McLafferty F. 2011. A century of progress in molecular mass spectrometry. Annu. Rev. Anal. Chem. 4:1-22
13. Henry K, Williams E, Wang B, McLafferty F, Shabanowitz J, Hunt D. 1989. Tumor-specific loss of 11p15.5 alleles in del11p13 Wilms tumor and in familial adrenocortical carcinoma. PNAS 86:3247-51
14. McLafferty F. 1994. High-resolution tandem FT mass spectrometry above 10 kDa. Acc. Chem. Res. 27:379-86
15. Kelleher N, Costello C, Begley T, McLafferty F. 1995. Thiaminase I (42 kDa) heterogeneity, sequence refinement, and active site location from high-resolution tandem mass spectrometry. J. Am. Soc. Mass Spectrom. 6:981-84
16. Compton P, Zamdborg L, Thomas P, Kelleher N. 2011. On the scalability and requirements of whole protein mass spectrometry. Anal. Chem. 83:6868-74
17. Zhou H, Ning Z, Starr A, Abu-FarhaM, Figeys D. 2012. Advancements in top-down proteomics. Anal. Chem. 84:720-34
18. Armirotti A, Damonte G. 2010. Achievements and perspectives of top-down proteomics. Proteomics 10:3566-76
19. Ahlf D, Thomas P, Kelleher N. 2013. Developing top down proteomics to maximize proteome and sequence coverage from cells and tissues. Curr. Opin. Chem. Biol. 17:787-94
20. Siuti N, Kelleher N. 2007. Decoding protein modifications using top-down mass spectrometry. Nat. Methods 4:817-21
21. Tran J, Doucette A. 2008. Rapid and effective focusing in a carrier ampholyte solution isoelectric focusing system: A proteome prefractionation tool. J. Proteome Res. 7:1761-66
22. Kelleher N, Taylor S, Grannis D, Kinsland C, Chiu H, et al. 1998. Efficient sequence analysis of the six gene products (7-74 kDa) from the Escherichia coli thiamine biosynthetic operon by tandem highresolution mass spectrometry. Protein Sci. 7:1796-801
23. Lee S, Berger S,Martinovic S, Pasa-Tolic L, Anderson G, et al. 2002. Direct mass spectrometric analysis of intact proteins of the yeast large ribosomal subunit using capillary LC/FTICR. PNAS 99:5942-47
24. Shen Y, Tolic N, Zhao R, Pasa-Tolic L, Li L, et al. 2001. High-throughput proteomics using highefficiency multiple-capillary liquid chromatography with on-line high-performance ESI FTICR mass spectrometry. Anal. Chem. 73:3011-21
25. Martinovic S, Berger S, Pasa-Tolic L, Smith R. 2000. Separation and detection of intact noncovalent protein complexes from mixtures by on-line capillary isoelectric focusing-mass spectrometry. Anal. Chem. 72:5356-60
26. Meng F, Cargile B, Patrie S, Johnson J, McLoughlin S, Kelleher N. 2002. Processing complex mixtures of intact proteins for direct analysis by mass spectrometry. Anal. Chem. 74:2923-29
27. Simpson D, Ahn S, Pasa-Tolic L, Bogdanov B, Mottaz H, et al. 2006. Using size exclusion chromatography-RPLC and RPLC-CIEF as two-dimensional separation strategies for protein profiling. Electrophoresis 27:2722-33
28. Ouvry-Patat S, Torres M, Quek H, Gelfand C, O'Mullan P, et al. 2008. Free-flow electrophoresis for top-down proteomics by Fourier transform ion cyclotron resonance mass spectrometry. Proteomics 8:2798-808
29. Smith R, Wahl J, Goodlett D, Hofstadler S. 1993. Capillary electrophoresis/mass spectrometry. Anal. Chem. 65:574A-84A
30. Valaskovic G, Kelleher N, McLafferty F. 1996. Attomole protein characterization by capillary electrophoresis-mass spectrometry. Science 273:1199-202
31. Li Y, Compton P, Tran J, Ntai I, Kelleher N. 2014. Optimizing capillary electrophoresis for top-down proteomics of 30-80 kDa proteins. Proteomics 14:1158-64
32. Zhao Y, Riley N, Sun L, Hebert A, Yan X, et al. 2015. Coupling capillary zone electrophoresis with electron transfer dissociation and activated ion electron transfer dissociation for top-down proteomics. Anal. Chem. 87:5422-29
33. Tran J, Doucette A. 2008. Gel-eluted liquid fraction entrapment electrophoresis: an electrophoretic method for broad molecular weight range proteome separation. Anal. Chem. 80:1568-73
34. Tran J, Doucette A. 2009. Multiplexed size separation of intact proteins in solution phase for mass spectrometry. Anal. Chem. 81:6201-9
35. Catherman A, Durbin K, Ahlf D, Early B, Fellers R, et al. 2013. Large-scale top-down proteomics of the human proteome: membrane proteins, mitochondria, and senescence. Mol. Cell. Proteom. 12:3465-73
36. Tran JC, Zamdborg L, Ahlf D, Lee J, Catherman A, et al. 2011. Mapping intact protein isoforms in discovery mode using top-down proteomics. Nature 480:254-58
37. Ahlf D, Compton P, Tran J, Early B, Thomas P, KelleherN. 2012. Evaluation of the compact high-field Orbitrap for top-down proteomics of human cells. J. Proteome Res. 11:4308-14
38. Catherman A, Li M, Tran J, Durbin K, Compton P, et al. 2013. Top down proteomics of human membrane proteins from enriched mitochondrial fractions. Anal. Chem. 85:1880-88
39. Ntai I, Kim K, Fellers R, Skinner O, Smith AD IV, et al. 2014. Applying label-free quantitation to top down proteomics. Anal. Chem. 86:4961-68
40. Kim K, Compton P, Tran J, Keleher N. 2015. Online matrix removal platform for coupling gel-based separations to whole protein electrospray ionization mass spectrometry. J. Proteome Res. 14:2199-206
41. Zinnel NF, Pai P-J, Russell DH. 2012. Ion mobility-mass spectrometry (IM-MS) for top-down proteomics: Increased dynamic range affords increased sequence coverage. Anal. Chem. 84:3390-97
42. Xiu L, Valeja S, Alpert A, Jin S, Ge Y. 2014. Effective protein separation by coupling hydrophobic interaction and reverse phase chromatography for top-down proteomics. Anal. Chem. 86:7899-906
43. Valeja S, Xiu L, Gregorich Z, Guner H, Jin S, Ge Y. 2015. Three dimensional liquid chromatography coupling ion exchange chromatography/hydrophobic interaction chromatography/reverse phase chromatography for effective protein separation in top-down proteomics. Anal. Chem. 87:5363-71
44. Denisov E, Damoc E, Lange O, Makarov A. 2012. Orbitrap mass spectrometry with resolving powers above 1,000,000. Int. J. Mass Spectrom. 325-27:80-85
45. Patrie S, Charlebois J, Whipple D, Kelleher N, Hendrickson C, et al. 2004. Construction of a hybrid quadrupole/Fourier transform ion cyclotron resonance mass spectrometer for versatile MS/MS above 10 kDa. J. Am. Soc. Mass Spectrom. 15:1099-108
46. Tolmachev A, Robinson E, Wu S, Pasa-Tolic L, Smith R. 2009. FT-ICR MS optimization for the analysis of intact proteins. Int. J. Mass Spectrom. 281:32-38
47. Hu Q, Noll R, Li H, Makarov A, Hardman M, Cooks R. 2005. The Orbitrap: A new mass spectrometer. J. Mass Spectrom. 40:430-43
48. Makarov A, Denisov E, Kholomeev A, Balschun W, Lange O, et al. 2006. Performance evaluation of a hybrid linear ion trap/Orbitrap mass spectrometer. Anal. Chem. 78:2113-20
49. Michalski A, Damoc E, Hauschild J, Lange O, Wieghaus A, et al. 2011. Mass spectrometry-based proteomics using Q Exactive, a high-performance benchtop quadrupole Orbitrap mass spectrometer. Mol. Cell. Proteom. 10:M111.011015
50. Macek B, Waanders L, Olsen J, Mann M. 2006. Top-down protein sequencing and MS3 on a hybrid linear quadrupole ion trap-Orbitrap mass spectrometer. Mol. Cell. Proteom. 5:949-58
51. Boyne M II, Pesavento J, Mizzen C, Kelleher N. 2006. Precise characterization of human histones in the H2A gene family by top down mass spectrometry. J. Proteome Res. 5:248-53
52. Thomas C, Kelleher N, Mizzen C. 2006. Mass spectrometric characterization of human histone H3: A bird's eye view. J. Proteome Res. 5:240-47
53. SiutiN,RothMJ, MizzenCA, KelleherNL, Pesavento JJ. 2006. Gene-specific characterization of human histone H2B by electron capture dissociation. J. Proteome Res. 5:233-39
54. Wynne C, Fenselau C, Demirev P, Edewards N. 2009. Top-down identification of protein biomarkers in bacteria with unsequenced genomes. Anal. Chem. 81:9633-42
55. Wynne C, Edwards N, Fenselau C. 2010. Phyloproteomic classification of unsequenced organisms by top-down identification of bacterial proteins using capLC-MS/MS on an Orbitrap. Proteomics 10:3631-43
56. Fornelli L, Parra J, Hartmer R, Stoermer C, Lubeck M, Tsybin Y. 2013. Top-down analysis of 30-80 kDa proteins by electron transfer dissociation time-of-flight mass spectrometry. Anal. Bioanal. Chem. 405:8505-14
57. Chamot-Rooke J,MikatyG,Malosse C, SoyerM,Dumont A, et al. 2011. Posttranslationalmodification of pili upon cell contact triggers N. meningitidis dissemination. Science 331:778-82
58. Zhurov K, Fornelli L, Wodrich M, Laskay U, Tsybin Y. 2012. Principles of electron capture and transfer dissociation mass spectrometry applied to peptide and protein structure analysis. Chem. Soc. Rev. 42:5014-30
59. McAlister G, Phanstiel D, Good D, Berggren W, Coon J. 2007. Implementation of electron-transfer dissociation on a hybrid linear ion trap-Orbitrap mass spectrometer. Anal. Chem. 79:3525-34
60. Fornelli L, Damoc E, Thomas P, Kelleher N, Aizikov K, et al. 2012. Analysis of intact monoclonal antibody IgG1 by electron transfer dissociation Orbitrap FTMS. Mol. Cell. Proteom. 11:1758-67
61. Mao Y, Valeja S, Rouse J, Hendrickson C, Marshall A. 2013. Top-down structural analysis of an intact monoclonal antibody by electron capture dissociation-Fourier transform ion cyclotron resonance-mass spectrometry. Anal. Chem. 85:4239-46
62. Ge Y, Rybakova I, Xu Q, Moss R. 2009. Top-down high-resolution mass spectrometry of cardiac myosin binding protein C revealed that truncation alters protein phosphorylation state. PNAS 106:12658-63
63. RileyN,Westphall M, Coon J. 2015. Activated ion electron transfer dissociation for improved fragmentation of intact proteins. Anal. Chem. 87:7109-16
64. Cannon J, Cammarata M, Robotham S, Cotham V, Shaw J, et al. 2014. Ultraviolet photodissociation for characterization of whole proteins on a chromatographic time scale. Anal. Chem. 86:2185-92
65. Warnke S, von Helden G, Pagel K. 2015. Analyzing the higher order structure of proteins with conformer-selective ultraviolet photodissociation. Proteomics 15:2804-12
66. Dang X, YoungN. 2014. Ultraviolet photodissociation enhances top-downmass spectrometry as demonstrated on green fluorescent protein variants. Proteomics 14:1128-29
67. Shaw J, Li W, Holden D, Zhang Y, Griep-Raming J, et al. 2013. Complete protein characterization using top-down mass spectrometry and ultraviolet photodissociation. J. Am. Chem. Soc. 135:12646-51
68. Senko M, Remes P, Canterbury J, Mathur R, Song Q, et al. 2013. Novel parallelized quadrupole/linear ion trap/Orbitrap tribrid mass spectrometer improving proteome coverage and peptide identification rates. Anal. Chem. 85:11710-14
69. Brunner A,Lossl P, Liu F,HuguetR,MullenC, et al. 2015. Benchmarking multiple fragmentationmethods on an Orbitrap fusion for top-down phospho-proteoform characterization. Anal. Chem. 87:4152-58
70. Zheng Y, Fornelli L, Compton P, Sharma S, Canterbury J, et al. 2016. Unabridged analysis of human histone H3 by differential top-down mass spectrometry reveals hypermethylated proteoforms from MMSET/NSD2 overexpression. Mol. Cell. Proteom. 15:776-90
71. Levy M, Gucinski A, Boyne M II. 2015. Primary sequence confirmation of a protein therapeutic using top down MS/MS and MS3. Anal. Chem. 87:6995-99
72. Coelho Graça D, Hartmer R, Jabs W, Beris P, Clerici L, et al. 2015. Identification of hemoglobin variants by top-down mass spectrometry using selected diagnostic product ions. Anal. Bioanal. Chem. 407:2837-45
73. Acosta-Martin AE, Coelho Graça D, Antinori P, Clerici L, Hartmer R, et al. 2013. Quantitative mass spectrometry analysis of intact hemoglobin a2 by precursor ion isolation and detection. Anal. Chem. 85:7971-75
74. Shevchenko A, Wilm M, Vorm O, Mann M. 1996. Mass spectrometric sequencing of proteins from silver-stained polyacrylamide gels. Anal. Chem. 68:850-58
75. Washburn MP, Wolters D, Yates JR 3rd. 2001. Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat. Biotechnol. 19:242-47
76. Wisniewski JR, Zougman A, Nagaraj N, Mann M. 2009. Universal sample preparation method for proteome analysis. Nat. Methods 6:359-62
77. Bunger M, Cargile B, Ngunjiri A, Bundy J, Stephenson JL Jr. 2008. Automated proteomics of E. coli via top-down electron-transfer dissociation mass spectrometry. Anal. Chem. 80:1459-67
78. Ferguson J, Wenger C, Metcalf W, KelleherN. 2009. Top-down proteomics reveals novel protein forms expressed in Methanosarcina acetivorans. J. Am. Soc. Mass Spectrom. 20:1743-50
79. Meng F, Du Y, Miller L, Patrie S, Robinson D, KelleherN. 2004. Molecular-level description of proteins from Saccharomyces cerevisiae using quadrupole FT hybrid mass spectrometry for top down proteomics. Anal. Chem. 76:2852-58
80. Kellie JF, Catherman AD, Durbin KR, Tran JC, Tipton JD, et al. 2011. Robust analysis of the yeast proteome under 50 kDa by molecular-mass-based fractionation and top-down mass spectrometry. Anal. Chem. 84: 209-15
81. Roth M, Parks B, Ferguson J, BoyneMII, Kelleher N. 2008. "Proteotyping": population proteomics of human leukocytes using top down mass spectrometry. Anal. Chem. 80:2857-66
82. Pesavento J, Mizzen C, KelleherN. 2006. Quantitative analysis of modified proteins and their positional isomers by tandem mass spectrometry: human histone H4. Anal. Chem. 78:4271-80
83. Zabrouskov V, Ge Y, Schwartz J, Walker J. 2008. Unraveling molecular complexity of phosphorylated human cardiac troponin I by top down electron capture dissociation/electron transfer dissociation mass spectrometry. Mol. Cell. Proteom. 7:1838-49
84. Ayaz-Guner S, Zhang J, Li L, Walker J, Ge Y. 2009. In vivo phosphorylation site mapping in mouse cardiac troponin I by high-resolution top-down electron capture dissociation mass spectrometry: Ser22/23 are the only sites basally phosphorylated. Biochemstry 48:8161-70
85. Dong X, Sumandea C, Chen Y, Garcia-Cazarin M, Zhang J, et al. 2012. Augmented phosphorylation of cardiac troponin I in hypertensive heart failure. J. Biol. Chem. 287:848-57
86. Zhang J, Dong X, Hacker T, Ge Y. 2010. Deciphering modifications in swine cardiac troponin I by top-down high-resolution tandem mass spectrometry. J. Am. Soc. Mass Spectrom. 21:940-48
87. Xu F, Xu Q, Dong X, Guy M, Guner H, et al. 2011. Top-down high-resolution electron capture dissociation mass spectrometry for comprehensive characterization of post-translational modifications in Rhesus monkey cardiac troponin I. Int. J. Mass Spectrom. 305:95-102
88. Du Y, Parks B, Sohn S, Kwast K, Kelleher N. 2006. Top-down approaches for measuring expression ratios of intact yeast proteins using Fourier transform mass spectrometry. Anal. Chem. 78:686-94
89. ParksB, JiangL,ThomasP,WengerC,RothM, et al. 2007. Top-down proteomics on a chromatographic time scale using linear ion trap Fourier transform hybrid mass spectrometers. Anal. Chem. 79:7984-91
90. Collier T, Hawkridge A, Georgianna D, Payne G, Muddiman D. 2008. Top-down identification and quantification of stable isotope labeled proteins from Aspergillus flavus using online nano-flow reversedphase liquid chromatography coupled to a LTQ-FTICR mass spectrometer. Anal. Chem. 80:4994-5001
91. Ong SE, Blagoev B, Kratchmarova I, Kristensen DB, Steen H, et al. 2002. Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol. Cell. Proteom. 1:376-86
92. Collier T, Sarkar P, Rao B, Muddiman D. 2010. Quantitative top-down proteomics of SILAC labeled human embryonic stem cells. J. Am. Soc. Mass Spectrom. 21:879-89
93. Thompson A, Schafer J, Kuhn K, Kiele S, Schwarz J, et al. 2003. Tandem mass tags: A novel quantification strategy for comparative analysis of complex protein mixtures by MS/MS. Anal. Chem. 75:1895-904
94. Hung C, Tholey A. 2012. Tandem mass tag protein labeling for top-down identification and quantification. Anal. Chem. 84:161-70
95. Wiener M, Sachs J, Deyanova E, Yates N. 2004. Differential mass spectrometry: A label-free LC-MS method for finding significant differences in complex peptide and protein mixtures. Anal. Chem. 76:6085-96
96. Mazur M, Cardasis H, Spellman D, Liaw A, Yates N, Hendrickson R. 2010. Quantitative analysis of intact apolipoproteins in human HDL by top-down differential mass spectrometry. PNAS 107:7728-33
97. Gomez SM, Nishio JN, Faull KF, Whitelegge JP. 2002. The chloroplast grana proteome defined by intact mass measurements from liquid chromatography mass spectrometry. Mol. Cell. Proteom. 1:46-59
98. Ryan C, Souda P, Halgand F,Wong D, Loo J, et al. 2010. Confident assignment of intact mass tags to human salivary cystatins using top-down Fourier-transform ion cyclotron resonance mass spectrometry. J. Am. Soc. Mass Spectrom. 21:908-17
99. Cabras T, Pisano E, Boi R, Olianas A, Manconi B, et al. 2009. Age-dependent modifications of the human salivary secretory protein complex. J. Proteome Res. 8:4126-34
100. Castagnola M, Messana I, Inzitari R, Fanali C, Cabras T, et al. 2008. Hypo-phosphorylation of salivary peptidome as a clue to the molecular pathogenesis of autism spectrum disorders. J. Proteome Res. 7:5327-32
101. Wu S, Brown J, Tolic N, Meng D, Liu X, et al. 2014. Quantitative analysis of human salivary glandderived intact proteome using top-down mass spectrometry. Proteomics 14:1211-22
102. Edwards RL, Griffiths P, Bunch J, Cooper HJ. 2012. Top-down proteomics and direct surface sampling of neonatal dried blood spots: diagnosis of unknown hemoglobin variants. J. Am. Soc. Mass Spectrom. 23:1921-30
103. Edwards RL, Griffiths P, Bunch J, Cooper HJ. 2014. Compound heterozygotes and beta-thalassemia: top-down mass spectrometry for detection of hemoglobinopathies. Proteomics 14:1232-38
104. Mao P, Wang D. 2014. Top-down proteomics of a drop of blood for diabetes monitoring. J. Proteome Res. 13:1560-69
105. Demirev PA, Feldman AB, Kowalski P, Lin JS. 2005. Top-down proteomics for rapid identification of intact microorganisms. Anal. Chem. 77:7455-61
106. Hummel M, Wigger T, Brockmeyer J. 2015. Characterization of mustard 2S albumin allergens by bottom-up, middle-down, and top-down proteomics: A consensus set of isoforms of Sin a 1. J. Proteome Res. 14:1547-56
107. Lagrain B, Brunnbauer M, Rombouts I, Koehler P. 2013. Identification of intact high molecular weight glutenin subunits from the wheat proteome using combined liquid chromatography-electrospray ionization mass spectrometry. PLOS ONE 8:e58682
108. Petris LD, Orre L, Kanter L, Pernemalm M, Koyi H, et al. 2009. Tumor expression of S100A6 correlates with survival of patients with stage I non-small-cell lung cancer. Lung Cancer 63:410-17
109. Zhang J, Guy MJ, Norman HS, Chen Y-C, Xu Q, et al. 2011. Top-down quantitative proteomics identified phosphorylation of cardiac troponin I as a candidate biomarker for chronic heart failure. J. Proteome Res. 10:4054-65
110. Desiderio C, D'Angelo L, Rossetti D, Iavarone F, Giardina B, et al. 2012. Cerebrospinal fluid top-down proteomics evidenced the potential biomarker role of LVV-and VV-hemorphin-7 in posterior cranial fossa pediatric brain tumors. Proteomics 12:2158-66
111. Cabras T, Pisano E, Montaldo C, Giuca M, Iavarone F, et al. 2013. Significant modifications of the salivary proteome potentially associated with complications of Down syndrome revealed by top-down proteomics. Mol. Cell. Proteom. 12:1844-52
112. Laouirem S, Faouder JL, Alexandrov T, Mestivier D, Leger T, et al. 2014. Progression from cirrhosis to cancer is associated with early ubiquitin post-translationalmodifications: identification of new biomarkers of cirrhosis at risk of malignancy. J. Pathol. 234:452-63
113. Iavarone F, Melis M, Platania G, Cabras T,Manconi B, et al. 2014. Characterization of salivary proteins of schizophrenic and bipolar disorder patients by top-down proteomics. J. Proteom. 103:15-22
114. Ye H, Mandal R, Catherman A, Thomas P, Kelleher N, et al. 2014. Top-down proteomics with mass spectrometry imaging: A pilot study towards discovery of biomarkers for neurodevelopmental disorders. PLOS ONE 9:e92831
115. Kellie JF, Higgs RE, Ryder JW,Major A, Beach TG, et al. 2014. Quantitative measurement of intact α-synuclein proteoforms from post-mortem control and Parkinson's disease brain tissue by intact protein mass spectrometry. Sci. Rep. 4:5797
116. Martelli C, Iavarone F, D'Angelo L, Arba M, Vincenzoni F, et al. 2015. Integrated proteomic platforms for the comparative characterization of medulloblastoma and pilocytic astrocytoma pediatric brain tumors: A preliminary study. Mol. BioSyst. 11:1668-83
117. Savaryn JP, Catherman AD, Thomas PM, Abecassis MM, Kelleher NL. 2013. The emergence of topdown proteomics in clinical research. Genome Med. 5:53