The emerging role of peptidyl-prolyl isomerase chaperones in tau oligomerization, amyloid processing, and Alzheimer's disease

Abstract

Peptidyl-prolyl cis/trans isomerases (PPIases), a unique family of molecular chaperones, regulate protein folding at proline residues. These residues are abundant within intrinsically disordered proteins, like the microtubule-associated protein tau. Tau has been shown to become hyperphosphorylated and accumulate as one of the two main pathological hallmarks in Alzheimer's disease, the other being amyloid beta (Ab). PPIases, including Pin1, FK506-binding protein (FKBP) 52, FKBP51, and FKBP12, have been shown to interact with and regulate tau biology. This interaction is particularly important given the numerous proline-directed phosphorylation sites found on tau and the role phosphorylation has been found to play in pathogenesis. This regulation then affects downstream aggregation and oligomerization of tau. However, many PPIases have yet to be explored for their effects on tau biology, despite the high likelihood of interaction based on proline content. Moreover, Pin1, FKBP12, FKBP52, cyclophilin (Cyp) A, CypB, and CypD have been shown to also regulate Ab production or the toxicity associated with Ab pathology. Therefore, PPIases directly and indirectly regulate pathogenic protein multimerization in Alzheimer's disease and represent a family rich in targets for modulating the accumulation and toxicity.

Keywords: Alzheimer's disease; PPIase; amyloid β; chaperone; immunophilin; tau.

Figure 1. Potential dual role of Proline-directed Ser/Thr motifs in tau

Tau contains 43 Proline residues in the human 441-residue isoform that could be modified by either PPIases or kinases. Many of these Prolines are grouped together in the Proline-rich domain between 151 and 244 αα. Within this domain, only 13 of the 23 Ser/Thr residues are known to be phosphorylated, suggesting that some of these sites may exist to regulate tau structure. PPIases could control both tau phosphorylation and tau structure leading to its oligomerization.