Lumbar Cerebrospinal Fluid Proteome in Multiple Sclerosis:  Characterization by Ultrafiltration, Liquid Chromatography, and Mass Spectrometry

Noben, Jean-Paul; Dumont, Debora; Kwasnikowska, Natalia; Verhaert, Peter; Somers, Veerle; Hupperts, Raymond; Stinissen, Piet; Robben, Johan

doi:10.1021/pr0504788

Cited by 71 publications

(66 citation statements)

References 84 publications

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“…Endogenous regulators modulate these two protease pathways as endogenous peptide inhibitors, activators, and in vivo secretory vesicle proteins. Neuropeptides in CSF (cerebrospinal fluid) in neurological diseases can monitor brain nervous activity since neuropeptides represent active neurotransmission (129,130).…”

Section: Future Perspectives -Linking Neuropeptide Mechanisms For Tramentioning

confidence: 99%

Proteases for Processing Proneuropeptides into Peptide Neurotransmitters and Hormones

Hook

Funkelstein

et al. 2008

Annu. Rev. Pharmacol. Toxicol.

220

304

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Summary Points List:1. Proteases are essential for proteolytic processing of proneuropeptide precursors into active peptide neurotransmitters and hormones.2. Secretory vesicles represent the primary subcellular site of neuropeptide biosynthesis, which are produced, stored, and secreted to mediate cell-cell communication. 3.Protease pathways for proneuropeptide processing have been elucidated consisting of (a) the newly identified cysteine protease cathepsin L with aminopeptidase B in secretory vesicles, and (b) the well-established, proprotein convertase family that include the neuroendocrine-specific prohormone convertases 1 and 2 (PC1/3 and PC2) with carboxypeptidase E. 4.Protease gene knockout experiments have validated the roles of PC1/3, PC2, as well as cathepsin L for the production of neuropeptides in nervous and endocrine tissues. 5.Endogenous regulators consisting of inhibitors and activators participate in the in vivo control of processing enzyme functions.6. Structural biology of protease and proneuropeptides will be important to understand interacting mechanisms for proneuropeptide processing. 7.Neuropeptidomics has recently been applied to investigations of neuropeptide systems for their primary sequence and structural identification, as well as quantitation by LC-MS/MS tandem mass spectrometry. 8.Proteomic studies have revealed functional protein families that participate in secretory vesicle functions for the production, storage, and secretion of neuropeptides.9. Pharmacological evaluation of unique specificities among neuropeptide processing systems will be valuable for design of future strategies to develop selective small molecule modulators of processing enzymes for therapeutic applications in health and disease.Future Issues: Areas of Neuropeptide Research for Exploration. 1.How are cathepsin L and prohormone convertase protease pathways coordinately regulated? 2.What is the proteolytic basis for tissue-specific processing of proneuropeptides, such as that for POMC?3. Selective and potent inhibitors of protease components for processing prohormones should be developed to facilitate basic and pharmacological research. 4.What are the structural features of prohormone and protease interactions for functional processing? Peptide neurotransmitters and peptide hormones, collectively known as neuropeptides, are required for cell-cell communication in neurotransmission and for regulation of endocrine functions. Neuropeptides are synthesized from protein precursors (termed proneuropeptides or prohormones) that require proteolytic processing primarily within secretory vesicles that store and secrete the mature neuropeptides to control target cellular and organ systems. This review describes interdisciplinary strategies that have elucidated two primary protease pathways for prohormone processing consisting of the cysteine protease pathway mediated by secretory vesicle cathepsin L and the well-known subtilisin-like proprotein convertase pathway that together support neuropeptide biosynthesis. Importantly...

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Section: Future Perspectives -Linking Neuropeptide Mechanisms For Tramentioning

confidence: 99%

Proteases for Processing Proneuropeptides into Peptide Neurotransmitters and Hormones

Hook

Funkelstein

et al. 2008

Annu. Rev. Pharmacol. Toxicol.

220

304

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“…Standardized sample handling is also important when trying to compare results between different laboratories (12)(13)(14). In the search for molecular biomarkers related to disorders of the central nervous system, CSF is the most promising biofluid because of its close contact to the affected tissue (13,(15)(16)(17)(18)(19)(20).…”

confidence: 99%

The Impact of Delayed Storage on the Measured Proteome and Metabolome of Human Cerebrospinal Fluid

et al. 2011

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BACKGROUND Because cerebrospinal fluid (CSF) is in close contact with diseased areas in neurological disorders, it is an important source of material in the search for molecular biomarkers. However, sample handling for CSF collected from patients in a clinical setting might not always be adequate for use in proteomics and metabolomics studies. METHODS We left CSF for 0, 30, and 120 min at room temperature immediately after sample collection and centrifugation/removal of cells. At 2 laboratories CSF proteomes were subjected to tryptic digestion and analyzed by use of nano-liquid chromatography (LC) Orbitrap mass spectrometry (MS) and chipLC quadrupole TOF-MS. Metabolome analysis was performed at 3 laboratories by NMR, GC-MS, and LC-MS. Targeted analyses of cystatin C and albumin were performed by LC–tandem MS in the selected reaction monitoring mode. RESULTS We did not find significant changes in the measured proteome and metabolome of CSF stored at room temperature after centrifugation, except for 2 peptides and 1 metabolite, 2,3,4-trihydroxybutanoic (threonic) acid, of 5780 identified peptides and 93 identified metabolites. A sensitive protein stability marker, cystatin C, was not affected. CONCLUSIONS The measured proteome and metabolome of centrifuged human CSF is stable at room temperature for up to 2 hours. We cannot exclude, however, that changes undetectable with our current methodology, such as denaturation or proteolysis, might occur because of sample handling conditions. The stability we observed gives laboratory personnel at the collection site sufficient time to aliquot samples before freezing and storage at −80 °C.

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“…To address these issues, a number of studies have applied a variety of novel proteomic approaches to the global analysis of biological fluids obtained from affected individuals including plasma and especially CSF. The overall goals of such studies were to create a databank of proteins found in the CSF of multiple sclerosis patients [43] and identify proteins that are uniquely detected in multiple sclerosis as compared to controls [28,44]. However, the search for unique disease markers by the analysis of the CSF presents multiple challenges.…”

Section: Challenges In the Proteomic Analysis Of The Csf From Multiplmentioning

confidence: 99%

“…A number of studies have used proteomic approaches in order to define the protein composition or identify differentially expressed proteins in the CSF of multiple sclerosis patients [28,43,44]. One of the investigations by 2-DE and MS compared CSF obtained from three multiple sclerosis patients with that of three individuals affected by other inflammatory conditions, two with CNS sarcoid and one with viral meningitis [28].…”

Section: Proteomic Analysis Of the Csf Obtained From Multiple Sclerosmentioning

confidence: 99%

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Proteomic strategies in multiple sclerosis and its animal models

Elkabes

2007

Proteomics Clinical Apps

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The early and precise diagnosis, the prognosis, and the clinical management of multiple sclerosis, remain a considerable challenge. In recent years, the development of novel and powerful proteomic techniques prompted the use of these approaches for the search of unique biomarkers in the cerebrospinal fluid of multiple sclerosis patients. A few studies have also utilized proteomics to delineate the profile of differentially expressed proteins in animal models of the human disease in order to gain global insights into affected pathways. The identification of differentially expressed proteins may be an initial step in the discovery of novel targets and mechanisms that play critical roles in the pathology of multiple sclerosis. Based on these findings, future investigations may elucidate the events leading to demyelination, axonal damage, and neurodegeneration, providing better insights into mechanisms governing the onset and progression of the disease. Although these proteomic studies provide valuable information, they are also faced with a number of challenges. The present review discusses some of the strengths and limitations of proteomic investigations as applied to multiple sclerosis.

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Lumbar Cerebrospinal Fluid Proteome in Multiple Sclerosis: Characterization by Ultrafiltration, Liquid Chromatography, and Mass Spectrometry

Cited by 71 publications

References 84 publications

Proteases for Processing Proneuropeptides into Peptide Neurotransmitters and Hormones

Proteases for Processing Proneuropeptides into Peptide Neurotransmitters and Hormones

The Impact of Delayed Storage on the Measured Proteome and Metabolome of Human Cerebrospinal Fluid

Proteomic strategies in multiple sclerosis and its animal models

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