Role of FK506 Binding Proteins in Neurodegenerative Disorders

S.      Chattopadhaya; A.      Harikishore; H.      S. Yoon

Abstract

Protein misfolding has been implicated in the pathophysiology of several neurodegenerative ‘amyloidoses’ that includes Alzheimers, Parkinsons, Huntingtons disease, frontotemporal dementia and amyotrophic lateral sclerosis. Accumulation of misfolded proteins into ordered fibrillar intra- or extracellular amyloids results in brain lesions that in turn lead to injury and neuronal loss. The appearance of protein aggregates in the diseased brain hints at an inability of cellular chaperones to properly assist folding of client proteins. Not surprisingly, studies involving cell-based and animal models of the neurodegenerative diseases have shown that overexpression of molecular chaperones can provide neuroprotection. Together with identification of new targets for symptomatic relief of motor and non-motor defects in neurodegenerative disorders, there is a critical unmet clinical need for the development of novel neuroprotective molecules. One such promising class of compounds are neuroimmunophilin ligands (NILs). Derived from FK506 (tacrolimus), NILs have been shown to be efficacious in a number of neurodegenerative disorders. The ability of these nonimmunosuppressive NILs to protect neurons is modulated, in part, by a large family of co-chaperone proteins called the FK506 binding proteins (FKBPs). This review focuses on the roles of FKBPs in neurodegenerative disorders with an emphasis on the cellular mechanisms responsible for their neuroprotective and neurotrophic activities. We discuss the structural features of FKBPs and the mode of action of NILs. For brevity, we limit our discussion to those FKBPs that are particularly enriched in the nervous system. We hope that such information will aid in the rational design of new and improved NILs for ameliorating neurodegenerative disorders.

Keywords: FK506 binding proteins FKBPs), neurodegenerative disorders, FK506 (Tacrolimus), PPIase activity, neuroimmunophilin ligand, pathophysiology, amyloidoses, frontotemporal dementia, amyotrophic lateral sclerosis, misfolded proteins, neuroimmunophilin ligand (NIL)