DISC1 Protects Against Zika Virus Infection and Long-Term Neurological Damage Through AMPK-mTOR-Mediated Autophagy
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ABSTRACT:
PROVIDER: PRJNA1222827 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32325481_1.fastq.gz | Fastqsanger.gz | |||
| SRR32325481_2.fastq.gz | Fastqsanger.gz | |||
| SRR32325482_1.fastq.gz | Fastqsanger.gz | |||
| SRR32325482_2.fastq.gz | Fastqsanger.gz | |||
| SRR32325483_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Disrupted in Schizophrenia 1 (DISC1) is essential for neuronal development and has been implicated in various psychiatric disorders. However, its role in Zika virus (ZIKV) infection, particularly in congenital Zika syndrome (CZS) and ZIKV-induced long-term neurodevelopmental defects, remains unexplored. In this study, we demonstrate that DISC1 suppresses ZIKV infection in human placental and neuroglia cells, as well as in murine macrophages. DISC1 also limits ZIKV dissemination from peripheral tissues to key organs of mice, including the uterus, testis, and brain, thereby reducing fetal abortion rates and intrauterine growth restriction. Notably, DISC1 is associated with long-term ZIKV effects, including memory loss, reduced anxiety and depression, declines in sociability and social novelty. Mechanistically, DISC1 activates autophagy by enhancing AMPKα phosphorylation and reducing mTOR phosphorylation, protecting against ZIKV infection. Additionally, DISC1 interacts with LC3 to further activate autophagy, partially contributing to inhibit ZIKV infection. In conclusion, DISC1 plays a critical factor in controlling ZIKV infection and mitigating CZS and ZIKV-induced neurocognitive decline.
2025-02-17 | GSE289385 | GEO
Project description:Disrupted in Schizophrenia 1 (DISC1) is essential for neuronal development and has been implicated in various psychiatric disorders. However, its role in Zika virus (ZIKV) infection, particularly in congenital Zika syndrome (CZS) and ZIKV-induced long-term neurodevelopmental defects, remains unexplored. In this study, we demonstrate that DISC1 suppresses ZIKV infection in human placental and neuroglia cells, as well as in murine macrophages. DISC1 also limits ZIKV dissemination from peripheral tissues to key organs of mice, including the uterus, testis, and brain, thereby reducing fetal abortion rates and intrauterine growth restriction. Notably, DISC1 is associated with long-term ZIKV effects, including memory loss, reduced anxiety and depression, declines in sociability and social novelty. Mechanistically, DISC1 activates autophagy by enhancing AMPKα phosphorylation and reducing mTOR phosphorylation, protecting against ZIKV infection. Additionally, DISC1 interacts with LC3 to further activate autophagy, partially contributing to inhibit ZIKV infection. In conclusion, DISC1 plays a critical factor in controlling ZIKV infection and mitigating CZS and ZIKV-induced neurocognitive decline.
2025-02-13 | PXD060751 |
Project description:Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we here combine a computational–experimental approach with text mining-enhanced quantitative proteomics. We report that AMP-activated protein kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR complex 2 (mTORC2) are acutely activated by aa-readdition in an mTORC1-independent manner. AMPK activation by aa is mediated by Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ). In response, AMPK impinges on the autophagy regulators Unc-51-like kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an mTORC1 antagonist that is activated by starvation. We find that aa acutely activate AMPK concurrently with mTOR. We show that AMPK under aa sufficiency acts to sustain autophagy. This may be required to maintain protein homoeostasis and deliver metabolite intermediates for biosynthetic processes.
2016-12-12 | PXD003073 | Pride
Project description:DallePezze2016 - Activation of AMPK and mTOR
by amino acids (Model 3)
This model is as described in
the Supplementary Software 3 of the reference publication: SBML
model similar to Model S2, but including a more complex p70-S6K
module.
This model is described in the article:
A systems study reveals
concurrent activation of AMPK and mTOR by amino acids.
Dalle Pezze P, Ruf S, Sonntag AG,
Langelaar-Makkinje M, Hall P, Heberle AM, Razquin Navas P, van
Eunen K, Tölle RC, Schwarz JJ, Wiese H, Warscheid B,
Deitersen J, Stork B, Fäßler E, Schäuble S, Hahn
U, Horvatovich P, Shanley DP, Thedieck K.
Nat Commun 2016 Nov; 7: 13254
Abstract:
Amino acids (aa) are not only building blocks for proteins,
but also signalling molecules, with the mammalian target of
rapamycin complex 1 (mTORC1) acting as a key mediator. However,
little is known about whether aa, independently of mTORC1,
activate other kinases of the mTOR signalling network. To
delineate aa-stimulated mTOR network dynamics, we here combine
a computational-experimental approach with text mining-enhanced
quantitative proteomics. We report that AMP-activated protein
kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR
complex 2 (mTORC2) are acutely activated by aa-readdition in an
mTORC1-independent manner. AMPK activation by aa is mediated by
Ca2+/calmodulin-dependent protein kinase kinase ? (CaMKK?). In
response, AMPK impinges on the autophagy regulators Unc-51-like
kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an
mTORC1 antagonist that is activated by starvation. We find that
aa acutely activate AMPK concurrently with mTOR. We show that
AMPK under aa sufficiency acts to sustain autophagy. This may
be required to maintain protein homoeostasis and deliver
metabolite intermediates for biosynthetic processes.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000640.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000640 | BioModels
Project description:Sonntag2012 - mTOR model - IRS dependent regulation of AMPK by insulin
TSC1-TSC2 complex has two states: 1)
active (TSC1_TSC2_pS1387), regulated by AMPK_pT172; 2) inactive
(TSC1_TSC2_pT1462) regulated by Akt_pT308. Particularly, mTORC1 is
inhibited by TSC1_TSC2 in active state. AMPK is activated at T172
by the species IRS1_p activated by the insulin receptor upon
insulin stimulation. Consequently, AMPK_pT172 is inhibited by
mTORC1_pS2448 indirectly by the p70-S6K-negative feedback loop.
This model is described in the article:
A modelling-experimental
approach reveals insulin receptor substrate (IRS)-dependent
regulation of adenosine monosphosphate-dependent kinase (AMPK)
by insulin.
Sonntag AG, Dalle Pezze P, Shanley
DP, Thedieck K.
FEBS J. 2012 Sep; 279(18):
3314-3328
Abstract:
Mammalian target of rapamycin (mTOR) kinase responds to
growth factors, nutrients and cellular energy status and is a
central controller of cellular growth. mTOR exists in two
multiprotein complexes that are embedded into a complex
signalling network. Adenosine monophosphate-dependent kinase
(AMPK) is activated by energy deprivation and shuts off
adenosine 5'-triphosphate (ATP)-consuming anabolic processes,
in part via the inactivation of mTORC1. Surprisingly, we
observed that AMPK not only responds to energy deprivation but
can also be activated by insulin, and is further induced in
mTORC1-deficient cells. We have recently modelled the mTOR
network, covering both mTOR complexes and their insulin and
nutrient inputs. In the present study we extended the network
by an AMPK module to generate the to date most comprehensive
data-driven dynamic AMPK-mTOR network model. In order to define
the intersection via which AMPK is activated by the insulin
network, we compared simulations for six different hypothetical
model structures to our observed AMPK dynamics. Hypotheses
ranking suggested that the most probable intersection between
insulin and AMPK was the insulin receptor substrate (IRS) and
that the effects of canonical IRS downstream cues on AMPK would
be mediated via an mTORC1-driven negative-feedback loop. We
tested these predictions experimentally in multiple set-ups,
where we inhibited or induced players along the insulin-mTORC1
signalling axis and observed AMPK induction or inhibition. We
confirmed the identified model and therefore report a novel
connection within the insulin-mTOR-AMPK network: we conclude
that AMPK is positively regulated by IRS and can be inhibited
via the negative-feedback loop.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000580.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000580 | BioModels
Project description:DallePezze2016 - Activation of AMPK and mTOR
by amino acids (Model 1)
This model is as described in
Supplementary Software 2 of the reference publication:
SBML
model including only the canonical amino acid input on
mTORC1.
This model is described in the article:
A systems study reveals
concurrent activation of AMPK and mTOR by amino acids.
Dalle Pezze P, Ruf S, Sonntag AG,
Langelaar-Makkinje M, Hall P, Heberle AM, Razquin Navas P, van
Eunen K, Tölle RC, Schwarz JJ, Wiese H, Warscheid B,
Deitersen J, Stork B, Fäßler E, Schäuble S, Hahn
U, Horvatovich P, Shanley DP, Thedieck K.
Nat Commun 2016 Nov; 7: 13254
Abstract:
Amino acids (aa) are not only building blocks for proteins,
but also signalling molecules, with the mammalian target of
rapamycin complex 1 (mTORC1) acting as a key mediator. However,
little is known about whether aa, independently of mTORC1,
activate other kinases of the mTOR signalling network. To
delineate aa-stimulated mTOR network dynamics, we here combine
a computational-experimental approach with text mining-enhanced
quantitative proteomics. We report that AMP-activated protein
kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR
complex 2 (mTORC2) are acutely activated by aa-readdition in an
mTORC1-independent manner. AMPK activation by aa is mediated by
Ca2+/calmodulin-dependent protein kinase kinase ? (CaMKK?). In
response, AMPK impinges on the autophagy regulators Unc-51-like
kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an
mTORC1 antagonist that is activated by starvation. We find that
aa acutely activate AMPK concurrently with mTOR. We show that
AMPK under aa sufficiency acts to sustain autophagy. This may
be required to maintain protein homoeostasis and deliver
metabolite intermediates for biosynthetic processes.
This model is hosted on
BioModels Database
and identified by:
MODEL1705030000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-05-18 | MODEL1705030000 | BioModels
Project description:DallePezze2016 - Activation of AMPK and mTOR
by amino acids (Model 2)
This
model is as described in the Supplementary Software 2 of the
reference publication:
SBML
model including four amino acids input in the network (simple
p70-S6K module).
This model is described in the article:
A systems study reveals
concurrent activation of AMPK and mTOR by amino acids.
Dalle Pezze P, Ruf S, Sonntag AG,
Langelaar-Makkinje M, Hall P, Heberle AM, Razquin Navas P, van
Eunen K, Tölle RC, Schwarz JJ, Wiese H, Warscheid B,
Deitersen J, Stork B, Fäßler E, Schäuble S, Hahn
U, Horvatovich P, Shanley DP, Thedieck K.
Nat Commun 2016 Nov; 7: 13254
Abstract:
Amino acids (aa) are not only building blocks for proteins,
but also signalling molecules, with the mammalian target of
rapamycin complex 1 (mTORC1) acting as a key mediator. However,
little is known about whether aa, independently of mTORC1,
activate other kinases of the mTOR signalling network. To
delineate aa-stimulated mTOR network dynamics, we here combine
a computational-experimental approach with text mining-enhanced
quantitative proteomics. We report that AMP-activated protein
kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR
complex 2 (mTORC2) are acutely activated by aa-readdition in an
mTORC1-independent manner. AMPK activation by aa is mediated by
Ca2+/calmodulin-dependent protein kinase kinase ? (CaMKK?). In
response, AMPK impinges on the autophagy regulators Unc-51-like
kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an
mTORC1 antagonist that is activated by starvation. We find that
aa acutely activate AMPK concurrently with mTOR. We show that
AMPK under aa sufficiency acts to sustain autophagy. This may
be required to maintain protein homoeostasis and deliver
metabolite intermediates for biosynthetic processes.
This model is hosted on
BioModels Database
and identified by:
MODEL1705030001.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-05-18 | MODEL1705030001 | BioModels
Project description:Purpose: Genetic and clinical association studies have identified disrupted-in-schizophrenia 1 (DISC1) as a candidate risk gene for major mental illness. DISC1 is interrupted by a balanced chr(1;11) translocation in a Scottish family, in which the translocation predisposes to psychiatric disorders. We investigate the consequences of DISC1 interruption in human neural cells using TALENs or CRISPR-Cas9 to target the DISC1 locus. We sought to compare the gene expression profiles of human neural progenitor cells (NPCs) and neurons with interruption of the DISC1 gene in exon 2 (affecting all known coding transcripts) or exon 8 (near the site of the Scottish translocation, affecting longer transcripts). Methods: Wild-type and DISC1-targeted iPSCs (wild-type = "WT", exon 8 single allelic frameshift mutant = "ex8_wm", exon 8 biallelic frameshift mutant = "ex8_mm", exon 2 biallelic frameshift mutant = "ex2mm") were differentiated to NPCs and neurons using an embryoid aggregate method. NPC or neuronal cultures were used for RNA harvest and subsequent paired-end stranded sequencing of >50M reads/sample and 3-6 biological replicates per group. Results: We find that a subset of genes related to neuronal differentiation and development are dysregulated with DISC1 disruption at the NPC timepoint, whereas expression of genes related to neuronal function and signaling are altered at the neuronal timepoint. This study implicates DISC1 as a regulator of neuronal development. mRNA profiles of wild-type and DISC1-targeted human iPSC-derived neural progenitor cells (day 17) and neurons (day 50) by paired-end sequencing, with 3-6 biological replicates, using Illumina HiSeq
2015-09-14 | E-GEOD-71289 | biostudies-arrayexpress
Project description:Background: One of the strongest identified risk factors for major psychiatric illness is a chromosomal translocation directly disrupting the DISC1 gene, which is observed in members of a large Scottish family. Although DISC1 is known to function through a variety of molecular pathways, no global assessment of the molecular consequences of cellular DISC1 perturbation has been carried out to date. Methods: Predicted effects of the t(1;11)(q42;q14) translocation on DISC1 expression were modelled in neural progenitor cells derived from human fetal cortex using RNA interference (RNAi). Downstream effects on the cellular transcriptome were assessed by microarray. The reproducibility of individual gene expression changes was tested in repeat experiments by quantitative PCR.Results: A total of 54 genes were differentially expressed between the DISC1 and control siRNA conditions at a false discovery rate (FDR) ⤠0.05 in the primary experiment. Differentially expressed genes were significantly over-represented in Gene Ontology terms relating to the cell cycle, but included genes involved in a variety of other functions. Several genes showing reproducible differences in gene expression have been previously implicated in psychiatric disorders. Most consistent gene expression differences were seen for CCND2, MEG3, SPOCK2 and GABRA5. Total RNA extracted from human neural progenitor cells manipulated with either of two siRNAs: control siRNA or siRNA targeting DISC1 . 3 replicates per group. Genome wide transcript levels were then measured using gene expression microarrays.
2016-03-01 | E-GEOD-35548 | biostudies-arrayexpress
Project description:Purpose: Genetic and clinical association studies have identified disrupted-in-schizophrenia 1 (DISC1) as a candidate risk gene for major mental illness. DISC1 is interrupted by a balanced chr(1;11) translocation in a Scottish family, in which the translocation predisposes to psychiatric disorders. We investigate the consequences of DISC1 interruption in human neural cells using TALENs or CRISPR-Cas9 to target the DISC1 locus. We sought to compare the gene expression profiles of human neural progenitor cells (NPCs) and neurons with interruption of the DISC1 gene in exon 2 (affecting all known coding transcripts) or exon 8 (near the site of the Scottish translocation, affecting longer transcripts). Methods: Wild-type and DISC1-targeted iPSCs (wild-type = "WT", exon 8 single allelic frameshift mutant = "ex8_wm", exon 8 biallelic frameshift mutant = "ex8_mm", exon 2 biallelic frameshift mutant = "ex2mm") were differentiated to NPCs and neurons using an embryoid aggregate method. NPC or neuronal cultures were used for RNA harvest and subsequent paired-end stranded sequencing of >50M reads/sample and 3-6 biological replicates per group. Results: We find that a subset of genes related to neuronal differentiation and development are dysregulated with DISC1 disruption at the NPC timepoint, whereas expression of genes related to neuronal function and signaling are altered at the neuronal timepoint. This study implicates DISC1 as a regulator of neuronal development.
2015-09-14 | GSE71289 | GEO