Seminar by Dr. Theo Rein
Max Planck Institute of Psychiatry, München (Germany)
FK506 binding protein 51 (FKBP51) is both regulator and target of the stress receptors. Genetic evidence implicated FKBP51 in stress-related psychiatric diseases such as depression and furthermore in the responsiveness to antidepressants. Since the molecular underpinnings remained elusive we set out to decipher intracellular pathways regulated by both antidepressants and FKBP51. Interaction analyses led to several convergently regulated molecular pathways in cells, mice and human. These pathways include GSK3beta, Akt1-Autophagy, and DNA methyltransferase 1 (DNMT1). Our studies characterize FKBP51 as remarkably versatile stress protein and scaffolder of multiple protein complexes. In patients suffering from depression, markers of these pathways predict clinical treatment response. To test whether these pathways might be causally involved in antidepressant action we used small molecules to address novel autophagy pathway components downstream of FKBP51. Some of them mimicked the action of antidepressants on autophagy pathway activity, changed synaptic function in vitro and in vivo and produced antidepressant-like behavioral effects in mice. These compounds thus provide a novel route to autophagy, reveal a particular form of neuronal autophagy, and identify novel compounds for autophagic therapy in psychiatric and other diseases.