Unraveling the Role of Peptidyl-Prolyl Isomerases in Neurodegeneration

Abstract

Immunophilins are a family of highly conserved proteins with a peptidyl-prolyl isomerase activity that binds immunosuppressive drugs such as FK506, cyclosporin A, and rapamycin. Immunophilins can be divided into two subfamilies, the cyclophilins, and the FK506 binding proteins (FKBPs). Next to the immunophilins, a third group of peptidyl-prolyl isomerases exist, the parvulins, which do not influence the immune system. The beneficial role of immunophilin ligands in neurodegenerative disease models has been known for more than a decade but remains largely unexplained in terms of molecular mechanisms. In this review, we summarize reported effects of parvulins, immunophilins, and their ligands in the context of neurodegeneration. We focus on the role of FKBP12 in Parkinson's disease and propose it as a novel drug target for therapy of Parkinson's disease.

Selective inhibitors of the FK506-binding protein 51 by induced fit

“…This is consistent with additional FKBP52 inhibition by high doses of FK506. FK506 analogs, also called neuroimmunophilin ligands, have been pursued for neurological disorders owing to their reported neuroactive properties 34,35 , but the underlying mechanisms have remained unclear 36 . Our findings show that inhibition of FKBP51 accounts, at least in part, for the neuritotrophic effects of neuroimmunophilin ligands.…”

FKBPs and their role in neuronal signaling

“…Several reports linked FKBP12 to protein aggregation [41]. FKBP12 was shown to bind to the intracellular domain of the amyloid precursor protein (APP), a key player in the pathogenesis of Alzheimer's disease [42].…”

Expeditious screening of candidate proteins for microbial vaccines

“…The cellular functions of PPIases include acting as chaperones as well as being accessory proteins in multi-protein complexes. PPIases are involved in diverse processes, from signal transduction to gene regulation at both the transcriptional and translational level (Göthel and Marahiel, 1999;Gerard et al, 2011). These enzymes fold proteins into an active configuration by catalyzing the slow cis/trans isomerization of proline-peptide bonds.…”