Analysis of the cerebellar molecular stress response led to first evidence of a role for FKBP51 in brain FKBP52 expression in mice and humans

Herrmann, Leonie; Ebert, Tim; Rosén, Helena; Novak, Božidar; Philipsen, Alexandra; Touma, Chadi; Schreckenbach, Monika; Gassen, Nils C.; Rein, Theo; Schmidt, Ulrike

doi:10.1016/j.ynstr.2021.100401

Cited by 8 publications

(2 citation statements)

References 53 publications

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“…For example and in contrast to FKBP52, FKBP51 is increased in different brain regions of patients with AD including the frontal and temporal cortex [114]. The latest observation is consistent with the recent study showing the ability of FKBP51 to modulate the expression of FKBP52 in the mouse brain and speculating for an inverse correlation between FKBP51 and FKBP52 expression levels in human brain [140]. FKBP12 immunoreactivity is also increased in the hippocampus and the frontal cortex of patients with AD and PD [16] whereas its expression is decreased in angular cortices of AD brains [53].…”

Section: Involvement Of Fkbp52 In Neurodegenerative Diseasessupporting

confidence: 88%

FKBP52 in Neuronal Signaling and Neurodegenerative Diseases: A Microtubule Story

Chambraud

Byrne

Meduri

et al. 2022

IJMS

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The FK506-binding protein 52 (FKBP52) belongs to a large family of ubiquitously expressed and highly conserved proteins (FKBPs) that share an FKBP domain and possess Peptidyl-Prolyl Isomerase (PPIase) activity. PPIase activity catalyzes the isomerization of Peptidyl-Prolyl bonds and therefore influences target protein folding and function. FKBP52 is particularly abundant in the nervous system and is partially associated with the microtubule network in different cell types suggesting its implication in microtubule function. Various studies have focused on FKBP52, highlighting its importance in several neuronal microtubule-dependent signaling pathways and its possible implication in neurodegenerative diseases such as tauopathies (i.e: Alzheimer disease) and alpha-synucleinopathies (i.e: Parkinson disease). This review summarizes our current understanding of FKBP52 actions in the microtubule environment, its implication in neuronal signaling and function, its interactions with other members of the FKBPs family and its involvement in neurodegenerative disease.

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Section: Involvement Of Fkbp52 In Neurodegenerative Diseasessupporting

confidence: 88%

FKBP52 in Neuronal Signaling and Neurodegenerative Diseases: A Microtubule Story

Chambraud

Byrne

Meduri

et al. 2022

IJMS

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“…Excluding direct action on HPA axis or hippocampal neurogenesis, the mechanism underlying stress-resilience effects of SAFit2 is likely complex as FKBP51 and its co-chaperone HSP90 are involved in numerous signaling pathways. SAFit2-mediated FKBP51 inhibition is expected to promote HSP90 and FKBP52 function [ 61 ]. It could be that stress resilience effects independent of GR-activity are mediated by HSP90.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis

et al. 2022

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Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.

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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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Analysis of the cerebellar molecular stress response led to first evidence of a role for FKBP51 in brain FKBP52 expression in mice and humans

Cited by 8 publications

References 53 publications

FKBP52 in Neuronal Signaling and Neurodegenerative Diseases: A Microtubule Story

FKBP52 in Neuronal Signaling and Neurodegenerative Diseases: A Microtubule Story

Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis

Genetically engineered mouse models of FK506‐binding protein 5

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