Immunophilins: new biomarkers and therapeutic targets for neurodegenerative diseases

[摘要] 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.

[发布机构] the University of Pittsburgh

[效力级别] HIV