ArticleActa neuropathologica2023
Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex.
Article in Acta neuropathologica, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 51 citations in OpenAlex.
- FKBP51: A new target for Parkinson's disease.Neural regeneration research · 2026Article
- Unraveling the enigma: Post-translational modifications in psychiatric disorders and their regulatory mechanisms.Journal of translational internal medicine · 2026Article
- Inhibition of FKBP51 alleviates depressive-like behaviors via AKT/mTOR-dependent autophagy and synaptic plasticity.The international journal of neuropsychopharmacology · 2026Article
- Decoding the cellular landscape of biological stress in the human brain.Neurobiology of stress · 2026Article
- Mapping spatially organized molecular and genetic signatures of schizophrenia across multiple scales in human prefrontal cortex.bioRxiv : the preprint server for biology · 2026Article
- Molecular pathways linking chronic psychological stress to accelerated aging: mechanisms and interventions.Frontiers in aging · 2026Review
- Review
- Human Brain Cell-Type-Specific Aging Clocks Based on Single-Nuclei Transcriptomics.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Single-cell, multi-region profiling of the macaque brain across the lifespan.bioRxiv : the preprint server for biology · 2025Article
- Cross-Tissue Specificity of Pediatric DNA Methylation Associated With Cumulative Family Stress.Developmental psychobiology · 2025Article
- Astrocytic glutamate regulation is shaped by adversity and glucocorticoid signalling.bioRxiv : the preprint server for biology · 2025Article
- CATT haplotype of the FKBP5 gene and dissociative phenomenology.Scientific reports · 2025Article
- Microglia Single-Cell RNA-Seq Enables Robust and Applicable Markers of Biological Aging.Aging cell · 2025Article
- Article
- Expanding our understanding of (mal)adapted stress physiology in psychiatric disorders: achieving single-cell characterisation of steroids and neuropeptides.Neurobiology of stress · 2025Review
- Stress-mediated Activation of Ferroptosis, Pyroptosis, and Apoptosis Following Mild Traumatic Brain Injury Exacerbates Neurological Dysfunctions.Molecular neurobiology · 2025Article
- FKBP5 Induces Senescence in BMSCs and Inhibits Osteogenic Differentiation Through the Canonical WNT/β-Catenin Signalling Pathway in Senile Osteoporosis.Journal of cellular and molecular medicine · 2025Article
- FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice.Nature communications · 2025Article
- Contrasting genetic predisposition and diagnosis in psychiatric disorders: A multi-omic single-nucleus analysis of the human OFC.Science advances · 2025Article
- FKBP51 inhibition ameliorates neurodegeneration and motor dysfunction in the neuromelanin-SNCA mouse model of Parkinson's disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
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36 authors at 13 institutions in 7 countries.
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Abstract
Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n = 1024) of FKBP5/1, examining neocortical areas (BA9, BA11 and ventral BA24/BA24a) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease state, ageing and genotype on cortical FKBP5/1 expression including in a cell type-specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq; BA9 and BA11) and targeted histology (BA9, BA24a), we established that these disease and ageing effects on FKBP5/1 expression were most pronounced in excitatory superficial layer neurons of the neocortex, and this effect appeared to be consistent in both the granular and agranular areas examined. We then found that this increase in FKBP5 levels may impact on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in superficial layer neurons in BA11. These findings pinpoint a novel cellular and molecular mechanism that has potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.
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