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Increased striatal mRNA and protein levels of the immunophilin FKBP-12 in experimental Parkinson’s Disease and identification of FKBP-12-binding proteins
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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2007 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 6, no 10, 3952-3961 p.Article in journal (Refereed) Published
Abstract [en]

FKBP-12, a 12 kDa FK506-binding protein (neuroimmunophilin), acts as a receptor for the immunosuppressant drug FK506. Neuroimmunophilins, including FKBP-12, are abundant in the brain and have been shown to be involved in reversing neuronal degeneration and preventing cell death. In this report, we have utilized several analytical techniques, such as in situ hybridization, Western blotting, two-dimensional gel electrophoresis, and liquid chromatography electrospray tandem mass spectrometry to study the transcriptional expression as well as protein levels of FKBP-12 in the unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease. The FKBP-12 protein was also detected directly on brain tissue sections using mass spectrometry profiling. We found increased levels of FKBP-12 mRNA and protein in the dorsal and middle part of the 6-OHDA lesioned striatum. Thus, these studies clearly demonstrate that FKBP-12 is increased in the brain of a common animal model of Parkinson's disease (PD). Additionally, we have identified potential binding partners to FKBP-12 that may be implicated in the pathophysiology of Parkinson's disease, such as alpha-enolase, 14-3-3 zeta/delta, pyruvate kinase isozymes, and heat shock protein 70, using surface plasmon resonance sensor technology in combination with mass spectrometry. In conclusion, these data strongly suggests that FKBP-12 is altered in an experimental model of PD.

Place, publisher, year, edition, pages
2007. Vol. 6, no 10, 3952-3961 p.
Keyword [en]
Parkinson's disease, proteomics, protein interactions, 6-OHDA, striatum, mass spectrometry
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-97678DOI: 10.1021/pr070189eISI: 000249983500010PubMedID: 17877381OAI: oai:DiVA.org:uu-97678DiVA: diva2:172711
Available from: 2008-11-06 Created: 2008-11-06 Last updated: 2011-01-20Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 84
peptidomics, mass spectrometry, liquid chromatography, MALDI imaging, neuropeptides, drugs, brain
National Category
Pharmacology and Toxicology
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
Available from: 2008-11-06 Created: 2008-11-06Bibliographically approved

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