FKBP51 modulates hippocampal size and function in post-translational regulation of Parkin.

Bin Qiu,Zhaohui Zhong,Weidong Yong,Kent E Williams,Shawn Righter,Tiebing Liang,Chao Wang,Yuxue Xu,Jun Wang,Gavriil Tsechpenakis,Yao-Ying Ma,Ran Deng

doi:10.1007/s00018-022-04167-8

Abstract

FK506-binding protein 51 (encoded by Fkpb51, also known as Fkbp5) has been associated with stress-related mental illness. To investigate its function, we studied the morphological consequences of Fkbp51 deletion. Artificial Intelligence-assisted morphological analysis revealed that male Fkbp51 knock-out (KO) mice possess more elongated dentate gyrus (DG) but shorter hippocampal height in coronal sections when compared to WT. Primary cultured Fkbp51 KO hippocampal neurons were shown to exhibit larger dendritic outgrowth than wild-type (WT) controls and pharmacological manipulation experiments suggest that this may occur through the regulation of microtubule-associated protein. Both in vitro primary culture and in vivo labeling support a role for FKBP51 in the regulation of microtubule-associated protein expression. Furthermore, Fkbp51 KO hippocampi exhibited decreases in βIII-tubulin, MAP2, and Tau protein levels, but a greater than 2.5-fold increase in Parkin protein. Overexpression and knock-down FKBP51 demonstrated that FKBP51 negatively regulates Parkin in a dose-dependent and ubiquitin-mediated manner. These results indicate a potential novel post-translational regulatory mechanism of Parkin by FKBP51 and the significance of their interaction on disease onset. KO has more flattened hippocampus using AI-assisted measurement Both pyramidal cell layer (PCL) of CA and granular cell layer (GCL) of DG distinguishable as two layers: deep cell layer and superficial layer.Distinct MAP2 expression between deep and superficial layer between KO and WT, Higher Parkin expression in KO brain Mechanism of FKBP51 inhibition resulting in Parkin, MAP2, Tau, and Tubulin expression differences between KO and WT mice, and resulting neurite outgrowth differences.

Highlights

FK506-binding protein 51 (FKBP51, encoded by Fkbp5) belongs to a subclass of immunophilin proteins and has peptidyl-prolyl cis–trans isomerase (PPIase) activity that is crucial for protein folding (Schiene and Fischer, 2000)
We examined the hippocampal morphology differences between Fkbp[51] knock-out (KO) and wild-type (WT) mice using Artificial Intelligence (AI) approach to determine the effects of Fkbp[51] ablation on neuronal development
The height of hippocampus was found to be shorter in KO than WT, the length of the cornu ammonis (CA) was found to be longer in KO than WT

Summary

Introduction

FK506-binding protein 51 (FKBP51, encoded by Fkbp5) belongs to a subclass of immunophilin proteins and has peptidyl-prolyl cis–trans isomerase (PPIase) activity that is crucial for protein folding (Schiene and Fischer, 2000). One of the well-studied functions of FKBP51 is its role as a co-chaperone of heat shock protein 90 (Hsp90) in the formation of the glucocorticoid receptor (GR) complex, which is a central contributor to the stress response that modifies the pathophysiology of stress-induced conditions (Schmidt et al, 2015; Szymanska et al, 2009; Tatro et al, 2010). Emerging data indicate that FKBP51 may play an important role in neuronal development, neurological diseases, and as a potential target for disease treatment (Gaali et al, 2015; Lieberman et al, 2016; Matosin et al, 2018; O'Leary et al, 2011; Schmidt et al, 2012; Wagner et al, 2012). Ample evidence supports the association between hippocampal volume and neurological and psychiatric diseases (Onoue et al, 2013; Smith, 2005; Thompson et al, 2004). No direct evidence from knocking out Fkbp[51] to support its role in hippocampal morphology and potential mechanism in disease development

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Conclusion