# Role of FK506 binding protein 51 in central nervous system diseases

## TL;DR

FKBP51 is a key protein involved in various central nervous system diseases, influencing disease progression and offering potential for new therapies.

## Contribution

This review highlights FKBP51's multifaceted role in CNS disorders and its potential as a therapeutic target.

## Key findings

- FKBP51 promotes Tau aggregation in Alzheimer's disease and affects neuronal survival in Parkinson's disease.
- FKBP51 influences mutant huntingtin clearance in Huntington's disease and worsens brain injury in stroke.
- FKBP51 has dual roles in glioma and is a target for new drugs and gene-editing therapies.

## Abstract

FK506-binding protein 51 (FKBP51) is a pivotal molecular chaperone and scaffolding protein that integrates and modulates multiple signaling pathways—including those involving HSP90, the glucocorticoid receptor, AKT, and NF-κB—through its FK1, FK2, and TPR domains, thereby playing a central role in the maintenance of central nervous system (CNS) homeostasis. This review systematically elaborates on the pathological mechanisms and therapeutic potential of FKBP51 in a variety of CNS disorders. In neurodegenerative diseases, FKBP51 promotes aberrant aggregation of Tau protein via the HSP90 complex, exacerbating the pathological progression of Alzheimer’s disease; in Parkinson’s disease, it influences neuronal survival through interaction with the PINK1/AKT signaling pathway; while in Huntington’s disease, it impairs the clearance of mutant huntingtin (mHTT) protein. In models of ischemic stroke, upregulation of FKBP51 enhances autophagy and inflammatory responses through pathways such as AKT/FoxO3, thereby amplifying brain injury. In glioma, FKBP51 exhibits a context-dependent dual role: it may exert tumor-suppressive effects by inhibiting Akt, while its splice variant FKBP51s can regulate PD-L1 expression, promoting tumor immune evasion and therapy resistance. Emerging highly selective small-molecule inhibitors, gene-editing technologies, and novel applications of conventional drugs targeting FKBP51 have demonstrated significant interventional potential in preclinical studies. In summary, FKBP51 constitutes a pleiotropic signaling node, positioning it as a prime therapeutic target for a broad spectrum of CNS disorders.