Increased Striatal mRNA and Protein Levels of the Immunophilin FKBP-12 in Experimental Parkinson's Disease and Identification of FKBP-12-Binding Proteins

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.

Inhibition of FK506 Binding Proteins Reduces α-Synuclein Aggregation and Parkinson's Disease-Like Pathology

“…If PPIases induce certain folds in ␣-SYN, the deregulation of their activity in conditions of oxidative stress might erroneously favor those conformations of ␣-SYN that lead to aggregation and toxicity. It was shown previously that striatal FKBP12 mRNA and protein levels are both increased in an experimental 6-OHDA model of PD (Nilsson et al, 2007). Moreover, a higher FKBP12 expression was reported in the brain of PD patients.…”

Imaging mass spectrometry to visualize biomolecule distributions in mouse brain tissue following hemispheric cortical spreading depression

“…CSD was unilaterally induced, enabling the contralateral hemisphere to be used as an internal control (as introduced by Andrén and workers for Parkinson's disease research [23,24] and recently used by Hanreider et al [25]). A SHAM-operated mouse, in which Na + instead of K + is applied to the brain surface and which does not result in CSD events, is included to control for possible changes related to the surgical procedures.…”

Intranasal Rapamycin Rescues Mice from Staphylococcal Enterotoxin B-Induced Shock

“…Rapamycin acts by binding to FKBP12, an immunophilin, blocking mTOC1 activity and inhibiting cell cycle progression and protein synthesis. In this regard, it is interesting that FKBP12 is also found in abundance in neuronal cells and blocking FKBP12 was reported to reverse neuronal degeneration [36]. Bidirectional crosstalk between the neuroendocrine and the immune system is critical in the elimination of pathogens and proinflammatory cytokines are known to act on the hypothalamus to modulate neuronal pathways [37].…”