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.