Immunophilins in neurodegeneration

Abstract

We have compelling evidence that immunophilins (IP), particularly FKBP12, can be used as early markers of neuronal degeneration in PD and experimental models of dopaminergic injury. Furthermore, our pilot studies suggest that treatment with IP ligands (IPL) may increase in vitro the expression of synaptic proteins suggesting a potential means of therapeutic intervention in chronic neurodegenerative diseases. To study in vitro the neurotrophic activities of IP and their response to neurotoxins we use two experimental systems: primary human neuroglial cultures and differentiated dopaminergic neuronal cell line SH-SY5Y. The assays used in these systems are gene silencing, western blotting, and immunofluorescence microscopy. Treatments with IPL (eg rapamycin) resulted in increased expression of dopamine transporter and synapsin. Treatment with dopaminergic neurotoxins like MPTP resulted in increased expression of FKBP12. To test our working hypothesis proposing that IP may play a protective role in the neuronal response to axonal and synaptic injury we are currently studying the protein-protein interactions between FKBP12 and synaptic modulators using co-precipitation and proteomics assays. Current studies target the role played by immunophilins in the axonal homeostasis and their response to synaptic injury. Our preliminary data suggest that IP may play an important role as chaperone for the proteins participating in the assembly of the synaptic apparatus, including neurotransmitter transporters, vesicle docking molecules and potentially calcium channel stabilizers. Our future studies will focus on the downstream effector molecules associated with the IP activity in normal and degenerating axons. Support provided by the CATER Fellowship, MIRM, UPitt.