Dataset Information

Stress enhances secretory autophagy increasing extracellular Bdnf maturation

ABSTRACT: Stress response is a fundamental mechanism to maintain a healthy homeostasis and its disruption is implicated in several psychiatric disorders. Autophagy is one of the mechanisms regulating homeostasis, and it is known to be activated by cellular stressors such as starvation. In a previous study, we revealed that glucocorticoid (GC)-mediated stress also activates macroautophagy via the stress-responsive co-chaperone FK506-binding protein 51 (FKBP51). In this study we reveal that GC-mediated stress enhances secretory autophagy, a recently described Atg-dependent secretory pathway, via FKBP51. Strikingly we detected the matrix metallopeptidase 9 (Mmp9) as one of the stress-induced secreted proteins. Furthermore we found that enhanced Mmp9 secretion increases both in vitro and in vivo the cleavage of pro-brain derived neurotrophic factor (proBdnf) to its mature form (mBdnf), a key protein in neuroplasticity. This unravelled mechanism can represent a link between stress and the development of psychiatric disorders.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Microglial Cell Line

SUBMITTER: Svenja Wiechmann

LAB HEAD: Bernhard Kuster

PROVIDER: PXD017076 | Pride | 2021-08-05

REPOSITORIES: Pride

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			Action	DRS
	03163_RA1_P036014_S00_A00_R1.raw	Raw
	03163_RA2_P036022_S00_A00_R1.raw	Raw
	03163_RA2_P036022_S00_A00_R2.raw	Raw
	03163_RB1_P036015_S00_A00_R1.raw	Raw
	03163_RB2_P036023_S00_A00_R1.raw	Raw

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Publications

Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion.

Martinelli Silvia S Anderzhanova Elmira A EA Bajaj Thomas T Wiechmann Svenja S Dethloff Frederik F Weckmann Katja K Heinz Daniel E DE Ebert Tim T Hartmann Jakob J Geiger Thomas M TM Döngi Michael M Hafner Kathrin K Pöhlmann Max L ML Jollans Lee L Philipsen Alexandra A Schmidt Susanne V SV Schmidt Ulrike U Maccarrone Giuseppina G Stein Valentin V Hausch Felix F Turck Christoph W CW Schmidt Mathias V MV Gellner Anne-Kathrin AK Kuster Bernhard B Gassen Nils C NC

Nature communications 20210730 1

The stress response is an essential mechanism for maintaining homeostasis, and its disruption is implicated in several psychiatric disorders. On the cellular level, stress activates, among other mechanisms, autophagy that regulates homeostasis through protein degradation and recycling. Secretory autophagy is a recently described pathway in which autophagosomes fuse with the plasma membrane rather than with lysosomes. Here, we demonstrate that glucocorticoid-mediated stress enhances secretory aut ...[more]

PMID: 34330919

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Project description:Early life stress (ELS) has often been described as a risk factor for developing psychiatric disease. However, moderate exposure to ELS can also lead to stress inoculation and consequently adaptive changes on brain and behavior. Moreover, the FKBP5 gene, encoding the FKBP51 co-chaperone, has been associated with an increased risk for developing psychiatric disorders, specifically in interaction with ELS exposure. However, the underlying mechanisms behind the interaction of FKBP51 and moderate ELS exposure are still not completely understood and particularly data in the female sex are scarce. In this study, the contribution of FKBP51 in glutamatergic forebrain neurons to the long-term consequences of moderate ELS was investigated in both sexes, by using the Fkbp5Nex conditional knockout line. In female wild-type Fkbp5lox/lox mice, ELS exposure led to an anxiolytic phenotype and improved memory performance in a stressful context, however this ELS effect was absent in in Fkbp5Nexx wild-type mice. Interactive effects of FKBP51 in glutamatergic forebrain neurons and moderate ELS exposure in female mice were also reflected on brain volume of different cortical regions, the subiculum and white matter structures. Furthermore, interactive effects were observed for structural and electrophysiological properties of CA1 pyramidal neurons of the dorsal hippocampus. RNA sequencing of the hippocampus revealed the transcription factor 4 (TCF4) as a potential regulator of these interactive effects. Cre-dependent viral overexpression of TCF4 in female Nex-Cre mice led to similar beneficial effects on behavior as the moderate ELS exposure. Taken together, this study shows that FKBP51 in glutamatergic forebrain neurons mediates adaptive effects of moderate ELS exposure on emotional regulation, cognitive behavior and neuronal structure and function. Moreover, it proposes TCF4 as an underlying target that drives the FKBP51-mediated effects of moderate ELS on brain and behavior.

Project description:While the paradigm that genetic predisposition and environmental exposures interact to shape development and function of the human brain and ultimately the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not been elucidated yet. Here we show that a functional polymorphism altering chromatin interaction between the transcription start site and long range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increases the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements (GREs) of FKBP5. This demethylation is linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global impact on the function of immune cells and brain areas associated with stress regulation. This first identification of molecular mechanisms of genotype-directed long-term environmental reactivity will also critically contribute to designing more effective treatment strategies for stress-related disorders. Effects of FKBP5 rs1360780 genotype x environment interaction on peripheral blood mRNA expression of GR responsive genes, as measured by gene expression arrays, were explored in 129 individuals (child abuse/risk allele carrier N = 40, child abuse/protective allele carrier N = 15; and no child abuse/risk allele carrier N = 60, no child abuse/protective allele carrier N = 14). In all 129 individuals, 1627 transcripts showed a significant correlation with plasma cortisol concentrations, suggesting their GR responsiveness. The correlation of 76 of these transcripts with cortisol plasma levels showed significant differences when stratifying by FKBP5 genotype in individuals with child abuse (Fisher z score ≥ 1.96) For these 76 transcripts, the mean absolute correlation coefficient with plasma cortisol was R = 0.23 in the risk allele carriers with child abuse, that is those exhibiting a demethylation of FKBP5 intron 7 as compared to R = 0.74 in the carriers of the protective genotype with child abuse where intron 7 methylation remains largely stable. This indicates a relative GR-resistance in the trauma exposed FKBP5 risk allele vs. protective genotype carriers. These 76 transcripts did not show a genotype-dependent difference in correlation coefficients in non-trauma exposed individuals suggesting that exposure to early trauma enhances FKBP5 genotype-dependent effect of GR sensitivity, most likely by epigenetic mechanisms. These findings suggest that the combination of FKBP5 risk allele carrier status and early trauma exposure alters the stress hormone-dependent regulation of several genes in peripheral blood cells, and might thereby enhance the reported association of early trauma with immune and inflammatory dysregulation, further promoting system-wide symptoms of stress-related disorders.