Integrated analysis of the cerebrospinal fluid peptidome and proteome.

Cerebrospinal fluid (CSF) is the only body fluid in direct contact with the brain and thus is a potential source of biomarkers. Furthermore, CSF serves as a medium of endocrine signaling and contains a multitude of regulatory peptides. A combined study of the peptidome and proteome of CSF or any other body fluid has not been reported previously. We report confident identification in CSF of 563 peptide products derived from 91 precursor proteins as well as a high confidence CSF proteome of 798 proteins. For the CSF peptidome, we use high accuracy mass spectrometry (MS) for MS and MS/MS modes, allowing unambiguous identification of neuropeptides. Combination of the peptidome and proteome data suggests that enzymatic processing of membrane proteins causes release of their extracellular parts into CSF. The CSF proteome has only partial overlap with the plasma proteome, thus it is produced locally rather than deriving from plasma. Our work offers insights into CSF composition and origin.

[1]  M. Yoshihara,et al.  The Synaptotagmins: Calcium Sensors for Vesicular Trafficking , 2004, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[2]  B. Strooper,et al.  The presenilins in Alzheimer's disease--proteolysis holds the key. , 1999, Science.

[3]  Jing Zhang,et al.  Quantitative proteomic analysis of age-related changes in human cerebrospinal fluid , 2005, Neurobiology of Aging.

[4]  P. Lombroso,et al.  Receptor and nonreceptor protein tyrosine phosphatases in the nervous system , 2003, Cellular and Molecular Life Sciences CMLS.

[5]  D. N. Perkins,et al.  Probability‐based protein identification by searching sequence databases using mass spectrometry data , 1999, Electrophoresis.

[6]  Matthias Mann,et al.  Identification of 491 proteins in the tear fluid proteome reveals a large number of proteases and protease inhibitors , 2006, Genome Biology.

[7]  A. Tashjian,et al.  Receptors for thyrotropin-releasing hormone in prolactin producing rat pituitary cells in culture. , 1973, The Journal of biological chemistry.

[8]  J. Scholz,et al.  Interaction of the amyloid precursor like protein 1 with the alpha2A-adrenergic receptor increases agonist-mediated inhibition of adenylate cyclase. , 2006, Cellular signalling.

[9]  J. Buxbaum,et al.  A critical role for the protein tyrosine phosphatase receptor type Z in functional recovery from demyelinating lesions , 2002, Nature Genetics.

[10]  May D. Wang,et al.  GoMiner: a resource for biological interpretation of genomic and proteomic data , 2003, Genome Biology.

[11]  M. Mann,et al.  Status of complete proteome analysis by mass spectrometry: SILAC labeled yeast as a model system , 2006, Genome Biology.

[12]  M. Mann,et al.  Stop and go extraction tips for matrix-assisted laser desorption/ionization, nanoelectrospray, and LC/MS sample pretreatment in proteomics. , 2003, Analytical chemistry.

[13]  X. Bertagna,et al.  Human joining peptide: a proopiomelanocortin product secreted as a homodimer. , 1988, Molecular endocrinology.

[14]  E. Rinderknecht,et al.  Polypeptides with nonsuppressible insulin-like and cell-growth promoting activities in human serum: isolation, chemical characterization, and some biological properties of forms I and II. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[15]  G. Abraham,et al.  Pyroglutamic acid , 1981, Molecular and Cellular Biochemistry.

[16]  R. Neumar,et al.  Proteins released from degenerating neurons are surrogate markers for acute brain damage , 2004, Neurobiology of Disease.

[17]  R. Palfree,et al.  Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Mann,et al.  Higher-energy C-trap dissociation for peptide modification analysis , 2007, Nature Methods.

[19]  S. Miyamoto,et al.  Heparin‐binding epidermal growth factor‐like growth factor as a novel targeting molecule for cancer therapy , 2006, Cancer science.

[20]  T. T. Chen,et al.  Recombinant E-peptides of pro-IGF-I have mitogenic activity. , 1999, Endocrinology.

[21]  D. Desiderio,et al.  Analysis of the human lumbar cerebrospinal fluid proteome , 2002, Electrophoresis.

[22]  E. Thompson,et al.  Laboratory Investigation of Cerebrospinal Fluid Proteins , 1990, Annals of clinical biochemistry.

[23]  J. Lah,et al.  Sortilin, SorCS1b, and SorLA Vps10p sorting receptors, are novel γ-secretase substrates , 2006, Molecular Neurodegeneration.

[24]  J. Ghiso,et al.  BRI2 INTERACTS WITH APP AND REGULATES A β PRODUCTION , 2005 .

[25]  J. Johansson,et al.  Peptide repertoire of human cerebrospinal fluid: novel proteolytic fragments of neuroendocrine proteins. , 2001, Journal of chromatography. B, Biomedical sciences and applications.

[26]  Martin Kuiper,et al.  BiNGO: a Cytoscape plugin to assess overrepresentation of Gene Ontology categories in Biological Networks , 2005, Bioinform..

[27]  D. Desiderio,et al.  Proteomics analysis of human cerebrospinal fluid. , 2005, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[28]  A. Fonteh,et al.  Protein Analysis in Human Cerebrospinal Fluid: Physiological Aspects, Current Progress and Future Challenges , 2005, Disease markers.

[29]  U. Vitt,et al.  Evolution and classification of cystine knot-containing hormones and related extracellular signaling molecules. , 2001, Molecular endocrinology.

[30]  M. Mann,et al.  The abc's (and xyz's) of peptide sequencing , 2004, Nature Reviews Molecular Cell Biology.

[31]  M. Mann,et al.  Parts per Million Mass Accuracy on an Orbitrap Mass Spectrometer via Lock Mass Injection into a C-trap*S , 2005, Molecular & Cellular Proteomics.

[32]  M. Mann,et al.  The human urinary proteome contains more than 1500 proteins, including a large proportion of membrane proteins , 2006, Genome Biology.

[33]  M. Mann,et al.  Improved peptide identification in proteomics by two consecutive stages of mass spectrometric fragmentation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Kaj Blennow,et al.  Proteomic studies of potential cerebrospinal fluid protein markers for Alzheimer's disease. , 2003, Brain research. Molecular brain research.

[35]  D. Desiderio,et al.  Proteomics analysis of prefractionated human lumbar cerebrospinal fluid , 2005, Proteomics.

[36]  L. Rodén.  Structure and Metabolism of Connective Tissue Proteoglycans , 1980 .

[37]  Rong-Fong Shen,et al.  Identification and proteomic profiling of exosomes in human urine. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[38]  R. Mentlein,et al.  Proline residues in the maturation and degradation of peptide hormones and neuropeptides , 1988, FEBS letters.

[39]  M. Alessio,et al.  Proteome study of human cerebrospinal fluid following traumatic brain injury indicates fibrin(ogen) degradation products as trauma-associated markers. , 2004, Journal of neurotrauma.

[40]  R. Mains,et al.  Peptidylglycine α‐amidating monooxygenase: A multifunctional protein with catalytic, processing, and routing domains , 1993, Protein science : a publication of the Protein Society.

[41]  M. Solimena,et al.  ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane protein of neurosecretory granules. , 1996, The EMBO journal.

[42]  Christian Haass,et al.  Amyloid Precursor-like Protein 1 Influences Endocytosis and Proteolytic Processing of the Amyloid Precursor Protein* , 2006, Journal of Biological Chemistry.

[43]  M. Jürgens,et al.  Screening for disulfide-rich peptides in biological sources by carboxyamidomethylation in combination with differential matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. , 2001, Rapid communications in mass spectrometry : RCM.

[44]  S. Carr,et al.  Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior , 1998, Cell.

[45]  E. Petricoin,et al.  The amplified peptidome: the new treasure chest of candidate biomarkers. , 2006, Current opinion in chemical biology.

[46]  F E Bloom,et al.  The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[47]  K. Grzeschik,et al.  The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor , 1987, Nature.

[48]  Matthias Mann,et al.  Large-scale and high-confidence proteomic analysis of human seminal plasma , 2006, Genome Biology.

[49]  J. Holton,et al.  Genetic alterations of the BRI2 gene: familial British and Danish dementias. , 2006, Brain pathology.

[50]  D. Desiderio,et al.  Human cerebrospinal fluid peptidomics. , 2005, Journal of mass spectrometry : JMS.

[51]  D. Steiner,et al.  Post-translational Processing of the Insulin-like Growth Factor-2 Precursor , 1998, The Journal of Biological Chemistry.

[52]  E. D. De Souza,et al.  Corticotropin-releasing factor receptors in the pituitary gland and central nervous system: methods and overview. , 1986, Methods in enzymology.

[53]  K. Blennow,et al.  Proteome studies of human cerebrospinal fluid and brain tissue using a preparative two‐dimensional electophoresis approach prior to mass spectrometry , 2001, Proteomics.

[54]  Lloyd D. Fricker,et al.  Neuropeptide-processing enzymes: Applications for drug discovery , 2005, The AAPS Journal.

[55]  Yan Liu,et al.  Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders. , 2006, Journal of Alzheimer's disease : JAD.

[56]  A. Johnsen,et al.  Alpha-amidated peptides derived from pro-opiomelanocortin in human pituitary tumours. , 1988, The Journal of endocrinology.

[57]  Kelvin H Lee,et al.  Towards two‐dimensional electrophoresis mapping of the cerebrospinal fluid proteome from a single individual , 2004, Electrophoresis.

[58]  T Bek,et al.  A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[59]  M. Westphal,et al.  A role for receptor tyrosine phosphataseζ in glioma cell migration , 2003, Oncogene.

[60]  J. Bixby,et al.  Growth Cone Steering by Receptor Tyrosine Phosphatase δ Defines a Distinct Class of Guidance Cue , 2000, Molecular and Cellular Neuroscience.

[61]  S. Hanash,et al.  Challenges in deriving high-confidence protein identifications from data gathered by a HUPO plasma proteome collaborative study , 2006, Nature Biotechnology.

[62]  C. Blobel,et al.  Remarkable roles of proteolysis on and beyond the cell surface. , 2000, Current opinion in cell biology.

[63]  R. Leduc,et al.  Subtilase-like pro-protein convertases: from molecular specificity to therapeutic applications. , 2000, Journal of molecular endocrinology.

[64]  Bruce R. Southey,et al.  NeuroPred: a tool to predict cleavage sites in neuropeptide precursors and provide the masses of the resulting peptides , 2006, Nucleic Acids Res..

[65]  T. Südhof,et al.  Neurexophilins Form a Conserved Family of Neuropeptide-Like Glycoproteins , 1998, The Journal of Neuroscience.

[66]  L. Jones,et al.  Phospholemman, a Single-Span Membrane Protein, Is an Accessory Protein of Na,K-ATPase in Cerebellum and Choroid Plexus , 2003, The Journal of Neuroscience.

[67]  Jing Zhang,et al.  Quantitative proteomics of cerebrospinal fluid from patients with Alzheimer disease. , 2005, Journal of Alzheimer's disease : JAD.

[68]  Jean-Paul Noben,et al.  Proteomic analysis of cerebrospinal fluid from multiple sclerosis patients , 2004, Proteomics.

[69]  R. Aebersold,et al.  Mass spectrometry in proteomics. , 2001, Chemical reviews.

[70]  T. Krieg,et al.  Serum xylosyltransferase: a new biochemical marker of the sclerotic process in systemic sclerosis. , 1999, The Journal of investigative dermatology.

[71]  J. Ghiso,et al.  BRI2 Interacts with Amyloid Precursor Protein (APP) and Regulates Amyloid β (Aβ) Production* , 2005, Journal of Biological Chemistry.

[72]  Kimberly Van Auken,et al.  WormBase: a multi-species resource for nematode biology and genomics , 2004, Nucleic Acids Res..

[73]  Emmanuel Mignot,et al.  Hypocretin/orexin, sleep and narcolepsy , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[74]  Agueda Rostagno,et al.  A stop-codon mutation in the BRI gene associated with familial British dementia , 1999, Nature.

[75]  R. Brumback.  Anatomic and Physiologic Aspects of the Cerebrospinal Fluid Space , 1989 .

[76]  M. Klagsbrun,et al.  Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein. , 1992, The Journal of biological chemistry.

[77]  Biaoyang Lin,et al.  A combined dataset of human cerebrospinal fluid proteins identified by multi‐dimensional chromatography and tandem mass spectrometry , 2007, Proteomics.

[78]  E. Birney,et al.  The International Protein Index: An integrated database for proteomics experiments , 2004, Proteomics.

[79]  Olivier Taboureau,et al.  Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus , 2005, Nature.