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

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

doi:10.1007/s00018-022-04167-8

Cited by 8 publications

(19 citation statements)

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“…3A. The identi cation of a functional connection between Parkin and FKBP51 (Qiu et al, 2022), along with the established relationship between Pink1 and FKBP51 (Boonying et al, 2019), strengthens the argument that FKBP51 plays an important role in mitochondrial regulation. Our study further pointed out those DEG with higher FC between KO and WT and their involved functions.…”

Section: Resultssupporting

confidence: 53%

“…STRING analysis identi ed inter-connections between Fkbp51, Hsp90aa1 and Park2, and a hub of genes related to lipid and TAG biosynthesis and metabolism, brogenesis, immune response, cell cycle, and drug metabolism. We have previously demonstrated FKBP51 and Parkin binding using immuno uorescence (IF) and co-immunoprecipitation (Qiu et al, 2022). In the current study, we found that these two proteins co-localize in mitochondria.…”

Section: Discussionsupporting

confidence: 57%

“…The hepatic brosis score was evaluated from eight randomly selected elds, as described (Dai et al, 2014). IHC was performed as previously described (Qiu et al, 2022). A list of antibodies used in this study is included in S-Table 4.…”

Section: Histological Analysis and Measurements Of Serum Cytokinesmentioning

confidence: 99%

“…Brie y, after indicated treatment, the cells were incubated with MitoTracker at a nal concentration of 200 nM at 37ºC for 30 min. After being washed with warmed DMEM and PBS, the cells were xed with 4% paraformaldehyde, and ICC was performed using anti-FKBP51, anti-Parkin, or anti-LC3 antibodies as previously described (Qiu et al, 2022). The uorescence signal was captured using confocal laser scanning microscopy (Leica TCS LSI, Germany).…”

Section: Histological Analysis and Measurements Of Serum Cytokinesmentioning

confidence: 99%

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Elimination of FKBP51 attenuates CCl4-induced liver injury via enhancement of mitochondrial function by increased Parkin activity

Qiu

Zhong

Dou

et al. 2023

Preprint

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Background & Aims Liver injury is a common feature of most chronic liver diseases. Previously, we found that Fkbp51 knockout (KO) mice resist high fat diet-induced fatty liver and alcohol-induced liver injury. The aim of this research is to identify the mechanism by which Fkbp51 affects liver injury using the carbon tetrachloride (CCl4) injection model. Methods CCl4-induced liver injury was compared between Fkbp51 KO and wild type (WT) mice. Step-wise and in-depth analyses were applied, including liver histology, biochemistry, RNA-Seq, mitochondrial respiration, electron microscopy, and molecular assessments. The selective FKBP51 inhibitor (SAFit2) was tested as a potential treatment to ameliorate liver injury. Results Fkbp51 knockout mice exhibited protection against liver injury, as evidenced by liver histology, reduced fibrosis-associated markers (Collagen I, α-SAM, CTGF, and TIMP1), and lower serum AST and ALT levels. RNA-seq identified differentially expressed genes between KO and WT after liver injury. Pathway and STRING analysis revealed that gene hubs involved in fibrogenesis, inflammation, mitochondria, and oxidative metabolism pathways are significantly altered and predicted the interaction of FKBP51, Parkin, and HSP90. Cellular studies supported co-localization of Parkin and FKBP51 in the mitochondrial network, and Parkin was shown to be expressed higher in the liver of KO mice at baseline and after liver injury relative to WT. Further functional analysis identified that KO mice exhibited increased ATP production and enhanced mitochondrial respiration. KO mice have increased mitochondrial size, increased autophagy/mitophagy and mitochondrial-derived vesicles (MDV), and reduced reactive oxygen species (ROS) production, which supports enhancement of mitochondrial quality control (MQC). Application of SAFit2, an FKBP51 inhibitor, reduced the effects of CCl4-induced liver injury and was associated with increased Parkin and ATP production. Conclusions Downregulation of FKBP51 represents a promising therapeutic target for the treatment of liver disease.

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Section: Resultssupporting

confidence: 53%

Section: Discussionsupporting

confidence: 57%

Section: Histological Analysis and Measurements Of Serum Cytokinesmentioning

confidence: 99%

Section: Histological Analysis and Measurements Of Serum Cytokinesmentioning

confidence: 99%

See 2 more Smart Citations

Elimination of FKBP51 attenuates CCl4-induced liver injury via enhancement of mitochondrial function by increased Parkin activity

Qiu

Zhong

Dou

et al. 2023

Preprint

Self Cite

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“…While, lowering the levels of FKBP5 reduced HTT in HD models both in vitro and in vivo [ 70 ]. FKBP5 knockout AD models exhibit few phenotypic changes or behavioral alterations [ 71 , 72 ] and, tau levels were reduced throughout the brains of Fkbp5 -/- mice [ 73 , 74 ]. These results supported the modulation of FKBP5 as a therapeutic target for neurological diseases.…”

Section: Discussionmentioning

confidence: 99%

Human microRNA-4433 (hsa-miR-4443) Targets 18 Genes to be a Risk Factor of Neurodegenerative Diseases

Yao

Zhang

et al. 2022

CAR

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Background: Neurodegenerative diseases, such as Alzheimer's disease patients (AD), Huntington's disease (HD) and Parkinson’s disease (PD), are common causes of morbidity, mortality, and cognitive impairment in older adults. Objective: We aimed to understand the transcriptome characteristics of the cortex of neurodegenerative diseases and to provide an insight into the target genes of differently expressed microRNAs in the occurrence and development of neurodegenerative diseases. Methods: The Limma package of R software was used to analyze GSE33000, GSE157239, GSE64977 and GSE72962 datasets to identify the differentially expressed genes (DEGs) and microRNAs in the cortex of neurodegenerative diseases. Bioinformatics methods, such as GO enrichment analysis, KEGG enrichment analysis and gene interaction network analysis, were used to explore the biological functions of DEGs. Weighted gene co-expression network analysis (WGCNA) was used to cluster DEGs into modules. RNA22, miRDB, miRNet 2.0 and TargetScan7 databases were performed to predict the target genes of microRNAs. Results: Among 310 Alzheimer's disease (AD) patients, 157 Huntington's disease (HD) patients and 157 non-demented control (Con) individuals, 214 co-DEGs were identified. Those co-DEGs were filtered into 2 different interaction network complexes, representing immune-related genes and synapse-related genes. The WGCNA results identified five modules: yellow, blue, green, turquoise, and brown. Most of the co-DEGs were clustered into the turquoise module and blue module, which respectively regulated synapse-related function and immune-related function. In addition, human microRNA-4433 (hsa-miR-4443), which targets 18 co-DEGs, was the only 1 co-up-regulated microRNA identified in the cortex of neurodegenerative diseases. Conclusion: 214 DEGs and 5 modules regulate the immune-related and synapse-related function of the cortex in neurodegenerative diseases. Hsa-miR-4443 targets 18 co-DEGs and may be a potential molecular mechanism in neurodegenerative diseases' occurrence and development.

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Genetically engineered mouse models of FK506‐binding protein 5

Gebru

Hill

Blair

2023

J of Cellular Biochemistry

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FK506 binding protein 51 (FKBP51) is a molecular chaperone that influences stress response. In addition to having an integral role in the regulation of steroid hormone receptors, including glucocorticoid receptor, FKBP51 has been linked with several biological processes including metabolism and neuronal health. Genetic and epigenetic alterations in the gene that encodes FKBP51, FKBP5, are associated with increased susceptibility to multiple neuropsychiatric disorders, which has fueled much of the research on this protein. Because of the complexity of these processes, animal models have been important in understanding the role of FKBP51. This review examines each of the current mouse models of FKBP5, which include whole animal knockout, conditional knockout, overexpression, and humanized mouse models. The generation of each model and observational details are discussed, including behavioral phenotypes, molecular changes, and electrophysiological alterations basally and following various challenges. While much has been learned through these models, there are still many aspects of FKBP51 biology that remain opaque and future studies are needed to help illuminate these current gaps in knowledge. Overall, FKBP5 continues to be an exciting potential target for stress‐related disorders.

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

Cited by 8 publications

References 97 publications

Elimination of FKBP51 attenuates CCl4-induced liver injury via enhancement of mitochondrial function by increased Parkin activity

Elimination of FKBP51 attenuates CCl4-induced liver injury via enhancement of mitochondrial function by increased Parkin activity

Human microRNA-4433 (hsa-miR-4443) Targets 18 Genes to be a Risk Factor of Neurodegenerative Diseases

Genetically engineered mouse models of FK506‐binding protein 5

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