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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

Anna Nilsson,^†^‡^# Karl Sköld,^†^‡^# Benita Sjögren,^§ Marcus Svensson,^†^‡ Johan Pierson,^† Xiaoqun Zhang,^§ Richard M. Caprioli, Jos Buijs, Björn Persson, Per Svenningsson,^§ and Per E. Andrén*^†^‡

Laboratory for Biological and Medical Mass Spectrometry, Uppsala University, P.O. Box 583 Biomedical Centre, SE-75123 Uppsala, Sweden, Department of Pharmaceutical Biosciences, Uppsala University, P.O. Box 591 Biomedical Centre, SE-751 24 Uppsala, Sweden, Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm, Sweden, Department of Medicinal Chemistry, Division of Analytical Pharmaceutical Chemistry, P.O. Box 574 Biomedical Centre, SE-751 23 Uppsala, Sweden, Mass Spectrometry Research Center, Vanderbilt University School of Medicine, 465 21 Avenue South, Room 9160 C, Nashville, Tennessee 37232-8575, and Biacore AB, Rapsgatan 7, 75450 Uppsala, Sweden

J. Proteome Res., 2007, 6 (10), pp 3952–3961

DOI: 10.1021/pr070189e

Publication Date (Web): September 18, 2007

†

Laboratory for Biological and Medical Mass Spectrometry, Uppsala University.

‡

Department of Pharmaceutical Biosciences, Uppsala University.

Equal contribution to this work.

Department of Physiology and Pharmacology, Karolinska Institute.

Department of Medicinal Chemistry, Uppsala University.

Vanderbilt University School of Medicine.

To whom correspondence should be addressed: Dr. Per E. Andrén, Laboratory for Biological and Medical Mass Spectrometry, Uppsala University, Box 583 Biomedical Centre, SE-75123 Uppsala, Sweden. Tel., +46 18 471 7206; fax, +46 18 471 4422. E-mail: per.andren@bmms.uu.se.

Abstract

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.

Keywords: Parkinson's disease • proteomics • protein interactions • 6-OHDA • striatum • mass spectrometry

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