Protein misfolding has been implicated in the pathophysiology of several neurodegenerative '
amyloidoses' that includes Alzheimer's, Parkinson's,
Huntington's 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.