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Striatal alterations of secretogranin-1, somatostatin, prodynorphin and cholecystokinin peptides in an experimental mouse model of Parkinson’s disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2009 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, Vol. 8, no 5, 1094-1104 p.Article in journal (Refereed) Published
Abstract [en]

The principal causative pathology of Parkinson disease is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta projecting to the striatum in the brain. The information regarding the expression of neuropeptides in parkinsonism is very limited. Here we have elucidated striatal neuropeptide mechanisms in experimental parkinsonism using the unilateral  6-hydroxydopamine model to degenerate dopamine neurons. A thoroughly controlled sample preparation technique together with a peptidomics approach and targeted neuropeptide sequence collections enabled sensitive detection, identification, and relative quantitation of a great number of endogenous neuropeptides. Previously not recognized alterations in neuropeptide levels were identified in the unilateral   lesioned mice with or without subchronic 3,4-dihydroxy-L-phenylalanine   administration, the conventional treatment of Parkinson disease. Several of these peptides originated from the same precursor such as secretogranin-1, somatostatin, prodynorphin, and cholecystokinin. Disease-related biotransformation of precursors into individual   peptides was observed in the experimental model of Parkinson disease. Several previously unreported potentially biologically active peptides were also identified from the striatal samples. This study provides further evidence that neuropeptides take part in mediating the central nervous system failure associated with Parkinson disease.

Place, publisher, year, edition, pages
2009. Vol. 8, no 5, 1094-1104 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97679DOI: 10.1074/mcp.M800454-MCP200ISI: 000266116900019OAI: oai:DiVA.org:uu-97679DiVA: diva2:172712
Available from: 2008-11-06 Created: 2008-11-06 Last updated: 2010-07-28Bibliographically approved
In thesis
1. Molecular Profiling and Imaging of Peptides, Proteins and Drugs in Biological Tissue using Mass Spectrometry
Open this publication in new window or tab >>Molecular Profiling and Imaging of Peptides, Proteins and Drugs in Biological Tissue using Mass Spectrometry
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Biological functions within cells and organisms are mainly carried out by the translational products; proteins and peptides. The analysis and characterization of these biomolecules are of great importance for the progress in disease research and biomarker and drug discovery. The term peptidomics was introduced to describe the comprehensive analysis of peptides (e.g. neuropeptides) in biological tissues. In this thesis, a peptidomics approach using nanoflow liquid chromatography coupled to electrospray mass spectrometry (MS) has been developed for detection, identification, and quantification of neuropeptides in different disease models. A thoroughly controlled sample preparation technique and targeted neuropeptide sequence collections have been used to improve sample quality and to increase the number of identified neuropeptides. In particular, neuropeptide changes in experimental models of Parkinson’s disease (PD), with or without L-DOPA treatment, and the effect of antidepressant treatment on neuropeptide expression have been investigated. Several novel, potentially bioactive, neuropeptides have been identified and a number of peptides derived from precursors such as secretogranin-1, preproenkephalin-B, and somatostatin have been found differentially expressed. Some of them represent novel findings, not previously associated with PD or treatment with antidepressants.

In addition, MALDI imaging MS (IMS), a technology that permits detection and spatial distribution determination of endogenous compounds and/or administered drugs directly on tissue sections, has been used in both small protein and drug applications. MALDI IMS on tissue samples from experimental models of PD revealed differential expression patterns of two small proteins involved in calcium regulation, PEP-19 and FKBP-12. Biomolecular interaction analysis was performed on FKBP-12 using surface plasmon resonance together with MS and several potential binding partners were identified.

In a second approach, MALDI IMS was used to study the distribution of the anticholinergic bronchodilator tiotropium in rat lung following inhalation of the drug. The distribution of the drug was monitored in both MS and MS/MS mode and the levels where linearly quantifiable in the range of 80 fmol – 5 pmol.

Conclusively, in this thesis mass spectrometry based technologies have successfully been developed to detect, identify, and characterize small proteins, peptides, and drugs in various tissue samples.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 84
Keyword
peptidomics, mass spectrometry, liquid chromatography, MALDI imaging, neuropeptides, drugs, brain
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-9337 (URN)978-91-554-7318-1 (ISBN)
Public defence
2008-11-28, B41, BMC, Husargatan 3, Uppsala, 10:15
Opponent
Supervisors
Available from: 2008-11-06 Created: 2008-11-06Bibliographically approved

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