IMMUNOPHILINS FKBP52 AND FKBP51 MODULATE GLUCOCORTICOID RECEPTOR DISTRIBUTION IN NEURONS AND ARE ALTERED IN HIV AND MAJOR DEPRESSIVE DISORDER

The class of proteins known as immunophilins, that are cis-trans prolyl isomerases perform diverse chaperone roles. The immunophilins FKBP52 and FKBP51 (FK506 Binding Proteins) are adapter proteins involved in the trafficking of the glucocorticoid receptor (GR), in which FKBP52 facilitates binding of retrograde molecular motor protein dynein and the GR, while FKBP51 binds only the GR. This body of work presents: 1. An analysis of the FKBP family of proteins and their potential for involvement of neuropathogenesis and identifies FKBP52 and FKBP51 as an evolutionarily divergent duo in mammals, 2. The changes in gene and protein levels of these immunophilins in the frontal cortex of patients with HIV and Major Depressive Disorder (MDD), and 3. A role for FKBP52 in the ligand-activated redistribution of GR in neurons.Using primary human mixed neuron-glia cultures, we tested the hypothesis that immunophilin ligands, like FK506, may alter the kinetics of FKBP52 or FKBP51-mediated trafficking of the GR in neurons. We treated the neuron-glia cultures with cortisol with or without FK506 pretreatment, and found that FK506 altered the distribution of GR. By knocking down expression of FKBP52 using siRNA in a differentiated neuroblastoma cell line, hydrocortisone-mediated nuclear translocation of GR was slowed. Treatment of neuroblastoma cells media supplemented with 10% conditioned media of HIV-infected microglia lead to increased expression of both immunophilins. In a parallel study, we assessed the transcriptional and postranscriptional levels of the GR adapter proteins FKBP52 and FKBP51 in autopsy tissues from the frontal cortex of patients with MDD with and without HIV. We found increased expression of both proteins in HIV infected patients. FKBP51 was increased in MDD while expression of FKBP52 was the highest in the HIV population with MDD.These data support the hypothesis that the immunophilins described here modulate the cellular function of the GR in the brain and expression levels may be related to mood disorders. In general, viral infection and inflammation increase expression, of both immunophilins, which may alter the cortisol-induced trafficking of GR