&lt;b&gt;&lt;i&gt;FKBP5&lt;/i&gt;&lt;/b&gt; Gene Variants May Modulate Depressive Features in Bipolar Disorder

Calabrò, Marco; Crisafulli, Concetta; Nicola, Marco Di; Colombo, Roberto; Janiri, Luigi; Serretti, Alessandro

doi:10.1159/000499976

Cited by 4 publications

(3 citation statements)

References 47 publications

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“…4l ). For example, ADAMTSL3 and VAV3 are considered candidate genes for schizophrenia 58 , 59 , and LTBP1 and FKBP5 are associated with depressive features in humans 60 , 61 . The high expression of genes associated with psychiatric disorders implies the potential role of these two clusters in emotional processing in humans.…”

Section: Resultsmentioning

confidence: 99%

Molecular and cellular evolution of the amygdala across species analyzed by single-nucleus transcriptome profiling

Zhang

Lin

et al. 2023

Cell Discov

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The amygdala, or an amygdala-like structure, is found in the brains of all vertebrates and plays a critical role in survival and reproduction. However, the cellular architecture of the amygdala and how it has evolved remain elusive. Here, we generated single-nucleus RNA-sequencing data for more than 200,000 cells in the amygdala of humans, macaques, mice, and chickens. Abundant neuronal cell types from different amygdala subnuclei were identified in all datasets. Cross-species analysis revealed that inhibitory neurons and inhibitory neuron-enriched subnuclei of the amygdala were well-conserved in cellular composition and marker gene expression, whereas excitatory neuron-enriched subnuclei were relatively divergent. Furthermore, LAMP5+ interneurons were much more abundant in primates, while DRD2+ inhibitory neurons and LAMP5+SATB2+ excitatory neurons were dominant in the human central amygdalar nucleus (CEA) and basolateral amygdalar complex (BLA), respectively. We also identified CEA-like neurons and their species-specific distribution patterns in chickens. This study highlights the extreme cell-type diversity in the amygdala and reveals the conservation and divergence of cell types and gene expression patterns across species that may contribute to species-specific adaptations.

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Section: Resultsmentioning

confidence: 99%

Molecular and cellular evolution of the amygdala across species analyzed by single-nucleus transcriptome profiling

Zhang

Lin

et al. 2023

Cell Discov

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“…97 Genetic variants of FKBP5 are correlated with an increased risk of alcohol dependence and EAU. [98][99][100][101] Moreover, FKBP5 is related to alcohol withdrawal severity. One study revealed that minor alleles of rs3800373 (G), rs9296158 (A), rs1360780 (T), and rs9470080 (T) in FKBP5 were significantly associated with lower Clinical Institute Withdrawal Assessment for Alcohol-Revised scores, whereas the minor alleles of rs3777747 (G) and rs9380524 (A) were associated with higher scores in 399 alcohol-dependent inpatients with alcohol consumption.…”

Section: Fkbp5 In Alcohol Drinking and Alcoholassociated Liver Diseasementioning

confidence: 99%

FK-binding protein 5: Possible relevance to the pathogenesis of metabolic dysfunction and alcohol-associated liver disease

Ma,

Yang,

Gao

et al. 2023

Journal of Investigative Medicine

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The FK506-binding protein (FKBP5) plays significant roles in mediating stress responses by interacting with glucocorticoids, participating in adipogenesis, and influencing various cellular pathways throughout the body. In this review, we described the potential role of FKBP5 in the pathogenesis of two common chronic liver diseases, metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD). We provided an overview of the FK-binding protein family, and elucidate their roles in cellular stress responses, metabolic diseases, and adipogenesis. We explored how FKBP5 may mechanistically influence the pathogenesis of MASLD and ALD and provided insights for further investigation into the role of FKBP5 in these two diseases.

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“…[7][8][9] Previous studies have linked genetic variants in FKBP5 to psychological disorders. [10][11][12] However, the role of FKBP5 in the heart has not been elucidated. In particular, it is not known whether dysregulation of FKBP5 in cardiomyocytes is involved in atrial arrhythmogenesis, which was the object of the present study.…”

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confidence: 99%

Downregulation of FKBP5 Promotes Atrial Arrhythmogenesis

Wang

Song

Yuan

et al. 2023

Circulation Research

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Background: Atrial fibrillation (AF), the most common arrhythmia, is associated with the downregulation of FKBP5 (encoding FKBP5 [FK506 binding protein 5]). However, the function of FKBP5 in the heart remains unknown. Here, we elucidate the consequences of cardiomyocyte-restricted loss of FKBP5 on cardiac function and AF development and study the underlying mechanisms. Methods: Right atrial samples from patients with AF were used to assess the protein levels of FKBP5. A cardiomyocyte-specific FKBP5 knockdown mouse model was established by crossbreeding Fkbp5 flox/flox mice with Myh6 MerCreMer/+ mice. Cardiac function and AF inducibility were assessed by echocardiography and programmed intracardiac stimulation. Histology, optical mapping, cellular electrophysiology, and biochemistry were employed to elucidate the proarrhythmic mechanisms due to loss of cardiomyocyte FKBP5. Results: FKBP5 protein levels were lower in the atrial lysates of patients with paroxysmal AF or long-lasting persistent chronic AF. Cardiomyocyte-specific knockdown mice exhibited increased AF inducibility and duration compared with control mice. Enhanced AF susceptibility in cardiomyocyte-specific knockdown mice was associated with the development of action potential alternans and spontaneous Ca 2+ waves, and increased protein levels and activity of the NCX1 (Na + /Ca 2+ -exchanger 1), mimicking the cellular phenotype of chronic AF patients. FKBP5-deficiency enhanced transcription of Slc8a1 (encoding NCX1) via transcription factor hypoxia-inducible factor 1α. In vitro studies revealed that FKBP5 negatively modulated the protein levels of hypoxia-inducible factor 1α by competitively interacting with heat-shock protein 90. Injections of the heat-shock protein 90 inhibitor 17-AAG normalized protein levels of hypoxia-inducible factor 1α and NCX1 and reduced AF susceptibility in cardiomyocyte-specific knockdown mice. Furthermore, the atrial cardiomyocyte-selective knockdown of FKBP5 was sufficient to enhance AF arrhythmogenesis. Conclusions: This is the first study to demonstrate a role for the FKBP5-deficiency in atrial arrhythmogenesis and to establish FKBP5 as a negative regulator of hypoxia-inducible factor 1α in cardiomyocytes. Our results identify a potential molecular mechanism for the proarrhythmic NCX1 upregulation in chronic AF patients.

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<b><i>FKBP5</i></b> Gene Variants May Modulate Depressive Features in Bipolar Disorder

Cited by 4 publications

References 47 publications

Molecular and cellular evolution of the amygdala across species analyzed by single-nucleus transcriptome profiling

Molecular and cellular evolution of the amygdala across species analyzed by single-nucleus transcriptome profiling

FK-binding protein 5: Possible relevance to the pathogenesis of metabolic dysfunction and alcohol-associated liver disease

Downregulation of FKBP5 Promotes Atrial Arrhythmogenesis

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