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Immunophilins: new biomarkers and therapeutic targets for neurodegenerative diseases

Avramut, Mihaela (2003) Immunophilins: new biomarkers and therapeutic targets for neurodegenerative diseases. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Immunophilins (IP) are receptors for immunosuppressive drugs like cyclosporin A, FK506, rapamycin and their analogs, which are collectively referred to as "immunophilin ligands" (IPL). The receptors for FK506 belong to the family of FK506- binding proteins (FKBP). Previous studies showed that FK506 augments neuronal growth in vitro. In animal models, the drug promotes morphologic and functional recovery following neuronal lesioning. Here we show for the first time that FK506 has neurotrophic effects in human brain primary cultures. Our data support a possible use of FK506 and its analogues in the treatment of neurodegenerative disorders and as adjuvants in neural tissue transplants. The effect of the drug in vivo, in patients, will ultimately depend on the presence and distribution of IP receptors in the normal and degenerating human brain.FKBP12, the archetypal member of the FKBP family, plays a role in protein folding, protein complexes assembly and intracellular calcium release. Crush injury of facial or sciatic nerves in rat leads to markedly increased FKBP12 levels in the respective nerve nuclei in parallel with nerve regeneration. The presence of FKBP IP has never been demonstrated in the human brain. Using light and immunofluorescent microscopy, laser confocal microscopy and western blotting, we studied FKBP12 expression in a set of archival brain material from Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies, encephalitic and non- encephalitic HIV- positive patients and age matched controls. We show that FKBP12 is present in the human brain, predominantly in neurons. Its levels and distribution are altered in the mid- frontal cortex, deep gray matter and midbrain of patients with neurodegenerative diseases. Moreover, it colocalizes with markers of pathology (Lewy bodies, neurofibrillary tangles and neuritic plaques) in areas of neurodegeneration. Disease- specific and region- specific changes are evident. Alterations in basal ganglia FKBP12 levels are also observed in MPTP- treated primates in association with dopaminergic loss (evidenced using PET functional imaging). We propose that the altered expression and distribution of FKBP12 is linked to abnormal protein folding and axonal transport. It may also reflect a compensatory regenerative response that renders immunophilins promising diagnostic and therapeutic targets.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Avramut, Mihaelaavramut@pitt.eduAVRAMUT
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairZeevi, Adrianazeevi@pitt.eduZEEVI
Committee CoChairAchim, Cristian
Committee MemberMichalopoulos, George K
Committee MemberZigmond, Michael
Committee MemberBowser, Robert
Date: 15 December 2003
Date Type: Completion
Defense Date: 25 November 2003
Approval Date: 15 December 2003
Submission Date: 9 December 2003
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: FKBP; HIV; immunophilins
Other ID:, etd-12092003-185626
Date Deposited: 10 Nov 2011 20:09
Last Modified: 15 Nov 2016 13:54


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