Immunophilins and their ligands: insights into survival and growth of human neurons.
The immunophilin receptors implicated in generating the neurotrophic effects of FK506 and rapamycin (RM) are unknown. Our studies are directed at (1) characterizing the effects of FK506 and RM on human fetal neurons and glia (2) revealing the role played by the immunophilin FKBP receptors and downstream effectors in mediating the effects of FK506 and RM on human brain cells and (3) clarifying the role of immunophilins (IP) in the normal and degenerating human brain. These studies provide the basis for the implementation of the FDA-approved immunophilin ligands (IPL) in the pharmacologic treatment of Parkinson's disease (PD). Additionally, they establish a potential link to pathogenetic and repair mechanisms associated with neurodegeneration and propose FKBP12 and FKBP52 as substrates that can be targeted by future drug design endeavors. Our studies also show for the first time that the immunophilin FKBP is present in the human brain and that its levels are altered in the brain of patients with neurodegenerative diseases. The increased levels of FKBP12 in neurons situated in areas of degeneration suggest that it may become a novel marker of pathology. Although the precise role of this immunophilin in the normal and degenerating brain awaits further clarification, this study suggests that FKBP might play a role in neuroprotection against abnormal protein aggregation, as well as participate in axonal transport and synaptic vesicle assembly. The rotamase activity of FKBP is likely to underlie these functions. If this hypothesis is confirmed, therapeutic attempts using rotamase activity-inhibiting immunophilin ligand administration in neurodegenerative disease patients need to be carefully designed.
Avramut
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Department of Pathology, University of Pittsburgh School of Medicine, S-406 Biomedical Science Tower, 200 Lothrop Street, 15213, Pittsburgh, PA, USA.
Achim
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D001921:Brain / Q000166:cytology / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D020104:Immunophilins / Q000502:physiology*; D008024:Ligands; D009474:Neurons / Q000502:physiology*
D008024:Ligands; D020104:Immunophilins