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PubMed: 30061532

Title
mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders.
Journal
International journal of molecular sciences
Volume
19
Issue
None
Pages
None
Date
2018-07-30
Authors
Busceti CL | Fornai F | Frati A | Limanaqi F | Ryskalin L

Evidence 127161fbc6
JSON

In addition, most DLB patients show most features of AD (i.e., hyperphosphorylated tau deposits and A beta) to various extents

a(CHEBI:"amyloid-beta") association path(MESH:"Lewy Body Disease") View Subject | View Object

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p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) association path(MESH:"Lewy Body Disease") View Subject | View Object

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path(MESH:"Lewy Body Disease") association p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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path(MESH:"Lewy Body Disease") association a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

Evidence 3bf90caf44
JSON

In fact, lithium is able to delay METH-induced sensitization, while being a powerful treatment in schizophrenia

a(CHEBI:"lithium(1+)") decreases path(MESH:Schizophrenia) View Subject | View Object

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a(CHEBI:"lithium(1+)") decreases act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

Evidence 40db20552f
JSON

Likewise, administration of either D1R agonists or METH enhances Akt activity and over-activates mTOR signaling

a(CHEBI:methamphetamine) increases act(p(FPLX:AKT)) View Subject | View Object

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a(CHEBI:methamphetamine) increases act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

act(p(HGNC:DRD1)) increases act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

act(p(HGNC:DRD1)) increases act(p(FPLX:AKT)) View Subject | View Object

Appears in Networks:

Evidence e06cf2c0c3
JSON

These pieces of evidence corroborate findings showing that several autophagy inducers, such as lithium, rapamycin, and Food and Drug Administration (FDA) approved antipsychotic drugs are effective to treat psychosis including schizophrenia

a(CHEBI:"lithium(1+)") decreases path(MESH:Schizophrenia) View Subject | View Object

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a(CHEBI:"lithium(1+)") decreases path(MESH:"Psychotic Disorders") View Subject | View Object

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a(CHEBI:sirolimus) decreases path(MESH:"Psychotic Disorders") View Subject | View Object

Appears in Networks:

a(CHEBI:sirolimus) decreases path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

a(MESH:"Antipsychotic Agents") decreases path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

a(MESH:"Antipsychotic Agents") decreases path(MESH:"Psychotic Disorders") View Subject | View Object

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Evidence 26f285ec0a
JSON

Again, rapamycin and rapalogs protect against toxicity produced by a number of misfolded proteins encompassing alpha synuclein, TDP43, and hyperphosphorylated tau

a(CHEBI:"mTOR inhibitor") decreases act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

a(CHEBI:"mTOR inhibitor") decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:

a(CHEBI:"mTOR inhibitor") decreases p(HGNC:SNCA, pmod(HBP:misfolded)) View Subject | View Object

Appears in Networks:

a(CHEBI:"mTOR inhibitor") decreases p(HGNC:TARDBP, pmod(HBP:misfolded)) View Subject | View Object

Appears in Networks:

a(CHEBI:sirolimus) decreases act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

a(CHEBI:sirolimus) decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:

a(CHEBI:sirolimus) decreases p(HGNC:SNCA, pmod(HBP:misfolded)) View Subject | View Object

Appears in Networks:

a(CHEBI:sirolimus) decreases p(HGNC:TARDBP, pmod(HBP:misfolded)) View Subject | View Object

Appears in Networks:

Evidence b6999c2e8b
JSON

Beyond METH, redox-related changes that result from an imbalance between reactive oxygen species (ROS) production and ROS clearance are implicated in schizophrenia

a(CHEBI:"reactive oxygen species") association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Schizophrenia) association a(CHEBI:"reactive oxygen species") View Subject | View Object

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Evidence c8a4cbea41
JSON

Both administration of amphetamines and stimulation of D1R induce a significant increase of CDK5 gene expression and protein levels, which, at molecular level, associates with increased dendritic spine density and hyper-phosphorylation of the cytoskeletal tau protein

a(CHEBI:amphetamine) increases g(HGNC:CDK5) View Subject | View Object

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a(CHEBI:amphetamine) increases p(HGNC:CDK5) View Subject | View Object

Appears in Networks:

a(GO:"dendritic spine") positiveCorrelation p(HGNC:CDK5) View Subject | View Object

Appears in Networks:

p(HGNC:CDK5) positiveCorrelation a(GO:"dendritic spine") View Subject | View Object

Appears in Networks:

p(HGNC:CDK5) positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:

act(p(HGNC:DRD1)) increases g(HGNC:CDK5) View Subject | View Object

Appears in Networks:

act(p(HGNC:DRD1)) increases p(HGNC:CDK5) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation p(HGNC:CDK5) View Subject | View Object

Appears in Networks:

Evidence e0e3039fc5
JSON

In contrast, chlorpromazine, which is a typical antipsychotic agent, induces autophagy by inhibiting the Akt/mTOR pathway

a(CHEBI:chlorpromazine) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

a(CHEBI:chlorpromazine) decreases bp(GO:"protein kinase B signaling") View Subject | View Object

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a(CHEBI:chlorpromazine) decreases act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

Evidence fdfc0950e5
JSON

Recently, in vitro studies on the effects of second-generation, atypical antipsychotics demonstrated that sertindole and clozapine are potent autophagy inducers in both neuronal and non-neuronal cell lines

a(CHEBI:clozapine) increases bp(GO:autophagy) View Subject | View Object

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a(CHEBI:sertindole) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

Evidence ff038edf21
JSON

Similar to pimozide, clozapine activates the autophagy process via the AMPK–ULK1–Beclin1 pathway, as evidenced by increased levels of autophagy markers (i.e., LC3-II and Atg5–Atg12 conjugate); increased phosphorylation of AMPK and its downstream substrates, namely ULK1 and beclin1; and an increased number of autophagosomes in the frontal cortex in clozapine-treated rats

a(CHEBI:clozapine) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

a(CHEBI:clozapine) increases p(HGNC:PRKAA1, pmod(Ph)) View Subject | View Object

Appears in Networks:

a(CHEBI:clozapine) increases p(HGNC:ULK1, pmod(Ph)) View Subject | View Object

Appears in Networks:

a(CHEBI:clozapine) increases p(HGNC:BECN1, pmod(Ph)) View Subject | View Object

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a(CHEBI:clozapine) increases a(GO:autophagosome) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Frontal Lobe

Evidence 1cfd9fd3d1
JSON

Chronic clozapine treatment (20 mg/kg/day) reduces Abeta deposition

a(CHEBI:clozapine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Frontal Lobe

Evidence 8d38cc4e3f
JSON

Accordingly, clinical evidence points towards an elevation of pre-synaptic DA synthesis and release as a key event for schizophrenia

a(CHEBI:dopamine) positiveCorrelation path(MESH:Schizophrenia) View Subject | View Object

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sec(a(CHEBI:dopamine)) association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Schizophrenia) positiveCorrelation a(CHEBI:dopamine) View Subject | View Object

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path(MESH:Schizophrenia) association sec(a(CHEBI:dopamine)) View Subject | View Object

Appears in Networks:

Evidence 6a5c97bfbd
JSON

In line with this, METH produces ultrastructural alterations reflecting dysfunctional autophagy flux, which are DA-dependent

a(CHEBI:dopamine) regulates bp(GO:autophagy) View Subject | View Object

Appears in Networks:

a(CHEBI:methamphetamine) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

Evidence eff1ffcc96
JSON

In fact, METH produces a massive increase of endogenous intra-cytosolic DA levels by inhibiting and reverting the direction of the vesicular monoamine transporter type 2 (VMAT-2), thus disrupting the physiological storage of DA

a(CHEBI:dopamine) association p(HGNC:SLC18A2) View Subject | View Object

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a(CHEBI:methamphetamine) increases a(CHEBI:dopamine, loc(GO:cytosol)) View Subject | View Object

Appears in Networks:

a(CHEBI:methamphetamine) decreases act(p(HGNC:SLC18A2)) View Subject | View Object

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p(HGNC:SLC18A2) association a(CHEBI:dopamine) View Subject | View Object

Appears in Networks:

Evidence b83071dc5e
JSON

It is worth mentioning that freely diffusible intra-cytosolic DA can readily undergo auto-oxidation and produce a cascade of oxidative-related damage, which is bound to the neurotoxic effects of high doses of METH

a(CHEBI:dopamine) increases bp(GO:"response to oxidative stress") View Subject | View Object

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a(CHEBI:methamphetamine) increases bp(GO:"response to oxidative stress") View Subject | View Object

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Evidence 05d7993f6a
JSON

In line with this, experimental models of DISC1 deficiency treated with METH show a significant potentiation of DA release, along with increased expression of D1R in the ventral striatum when compared with controls

sec(a(CHEBI:dopamine)) association a(CHEBI:methamphetamine) View Subject | View Object

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a(CHEBI:methamphetamine) association p(HGNC:DRD1) View Subject | View Object

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a(CHEBI:methamphetamine) association sec(a(CHEBI:dopamine)) View Subject | View Object

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p(HGNC:DRD1) association a(CHEBI:methamphetamine) View Subject | View Object

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Evidence 0bc1490ed5
JSON

For instance, haloperidol occludes huntingtin aggregation

a(CHEBI:haloperidol) decreases a(HBP:"huntingtin aggregates") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Frontal Lobe

Evidence 0accd326eb
JSON

As detailed in the following paragraph, METH exerts disruptive effects on DA neurotransmission, which translate into abnormal stimulation of post-synaptic DA receptors, mainly D1-type DA receptors (D1R), thus leading to non-canonical signaling cascades sustaining behavioral alterations that overlap with schizophrenia-like symptoms (i.e., visual and auditory hallucinations and delusions)

a(CHEBI:methamphetamine) decreases bp(GO:"dopamine secretion, neurotransmission") View Subject | View Object

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a(CHEBI:methamphetamine) decreases act(p(HGNCGENEFAMILY:"Dopamine receptors")) View Subject | View Object

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a(CHEBI:methamphetamine) decreases act(p(HGNC:DRD1)) View Subject | View Object

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a(CHEBI:methamphetamine) increases bp(GO:"non-canonical Wnt signaling pathway") View Subject | View Object

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a(CHEBI:methamphetamine) increases path(MESH:Hallucinations) View Subject | View Object

Appears in Networks:

a(CHEBI:methamphetamine) increases path(MESH:Delusions) View Subject | View Object

Appears in Networks:

path(MESH:Delusions) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

path(MESH:Hallucinations) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association path(MESH:Hallucinations) View Subject | View Object

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path(MESH:Schizophrenia) association path(MESH:Delusions) View Subject | View Object

Appears in Networks:

Evidence e3082578a9
JSON

These findings strongly suggest that an autophagy dysfunction acts both at pre- and post-synaptic level to alter DA neurotransmission during both METH administration and schizophrenia (Figure 2)

a(CHEBI:methamphetamine) association bp(GO:"dopamine secretion, neurotransmission") View Subject | View Object

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a(CHEBI:methamphetamine) decreases sec(a(CHEBI:dopamine)) View Subject | View Object

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bp(GO:"dopamine secretion, neurotransmission") association a(CHEBI:methamphetamine) View Subject | View Object

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bp(GO:"dopamine secretion, neurotransmission") association bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Schizophrenia

bp(GO:autophagy) decreases sec(a(CHEBI:dopamine)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Schizophrenia

bp(GO:autophagy) association bp(GO:"dopamine secretion, neurotransmission") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Schizophrenia

Evidence 3df0e401c0
JSON

In addition, several susceptibility genes for schizophrenia (e.g., DISC1, NRG1/ErbB4, and CRMP2), which are involved in either pre-synaptic DA release or post-synaptic D1R-related cascades, are similarly dysregulated by METH. Interestingly, they all converge on mTOR signaling (see Section 6, Table 1).

a(CHEBI:methamphetamine) decreases act(g(HGNC:DISC1)) View Subject | View Object

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a(CHEBI:methamphetamine) decreases act(g(HGNC:NRG1)) View Subject | View Object

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a(CHEBI:methamphetamine) decreases act(g(HGNC:DPYSL2)) View Subject | View Object

Appears in Networks:

g(HGNC:DISC1) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

act(g(HGNC:DISC1)) association act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

g(HGNC:DPYSL2) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

act(g(HGNC:DPYSL2)) association act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

g(HGNC:NRG1) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

act(g(HGNC:NRG1)) association act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) association act(g(HGNC:DISC1)) View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) association act(g(HGNC:NRG1)) View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) association act(g(HGNC:DPYSL2)) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association g(HGNC:DISC1) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association g(HGNC:NRG1) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association g(HGNC:DPYSL2) View Subject | View Object

Appears in Networks:

Evidence 650700ae86
JSON

In humans, the sensitizing effects of prolonged chronic METH intake are considered a major determinant to the occurrence and relapse of psychoses, which mirror those occurring in schizophrenic patients

a(CHEBI:methamphetamine) increases path(MESH:"Psychoses, Substance-Induced") View Subject | View Object

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path(MESH:"Psychotic Disorders") association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Schizophrenia) association path(MESH:"Psychotic Disorders") View Subject | View Object

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Evidence f18ff95384
JSON

Such an abnormal DA release produces peaks of extracellular DA, which cannot be taken up within nerve terminals, because METH inhibits and reverts the direction of the dopamine transporter (DAT).

a(CHEBI:methamphetamine) decreases act(p(HGNC:SLC6A3)) View Subject | View Object

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a(CHEBI:methamphetamine) decreases a(CHEBI:dopamine, loc(MESH:"Nerve Endings")) View Subject | View Object

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p(HGNC:SLC6A3) increases a(CHEBI:dopamine, loc(MESH:"Nerve Endings")) View Subject | View Object

Appears in Networks:

Evidence 573735ff42
JSON

In line with this, recent studies suggest that DAT expression is significantly reduced in the midbrain of postmortem schizophrenic samples [150], which is reminiscent of the METH-addicted brain [151,152].

a(CHEBI:methamphetamine) decreases p(HGNC:SLC6A3) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:Schizophrenia) decreases p(HGNC:SLC6A3) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Mesencephalon

Evidence 388727cce2
JSON

A reduction in VMAT-2 gene expression and protein levels in DA neurons occurs in both METH models and schizophrenic patients, marking quite impressively the overlap between these disorders

a(CHEBI:methamphetamine) negativeCorrelation p(HGNC:SLC18A2) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
dopaminergic neuron

p(HGNC:SLC18A2) negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
dopaminergic neuron

p(HGNC:SLC18A2) negativeCorrelation a(CHEBI:methamphetamine) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
dopaminergic neuron

path(MESH:Schizophrenia) negativeCorrelation p(HGNC:SLC18A2) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
dopaminergic neuron

Evidence 33bb0ba41b
JSON

Notably, high-throughput image-based screens performed by Zhang et al. (2007) [60] on a human glioblastoma H4 cell line expressing human LC3 coupled with green fluorescent protein (GFP) led us to disclose that three typical antipsychotic drugs (fluspirilene, trifluoperazine, and pimozide) are effective autophagy inducers.

a(CHEBI:pimozide) increases bp(GO:autophagy) View Subject | View Object

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a(CHEBI:trifluoperazine) increases bp(GO:autophagy) View Subject | View Object

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a(PUBCHEM:3396) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

Evidence 85f585abf3
JSON

For instance, the increase in autophagy flux induced by pimozide occurs along with a depression of phosphorylated tau in a transgenic mouse model of AD

a(CHEBI:pimozide) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Frontal Lobe
MeSH
Alzheimer Disease

a(CHEBI:pimozide) decreases p(MGI:Mapt, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Frontal Lobe
MeSH
Alzheimer Disease

Evidence 147ada64cf
JSON

In particular, pimozide provides an mTOR-independent autophagy induction, because it directly activates AMPK1, which in turn promotes autophagy through the phosphorylation of ULK1

a(CHEBI:pimozide) increases act(p(HGNC:PRKAA1)) View Subject | View Object

Appears in Networks:

act(p(HGNC:PRKAA1)) increases p(HGNC:ULK1, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:ULK1, pmod(Ph)) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

Evidence c98c82b084
JSON

This is further supported by mounting evidence obtained in rodent models, which demonstrate that rapamycin normalizes impaired social interactions and reverses behavioral defects

a(CHEBI:sirolimus) increases path(MESH:"Interpersonal Relations") View Subject | View Object

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a(CHEBI:sirolimus) increases bp(GO:behavior) View Subject | View Object

Appears in Networks:

Evidence bf613de225
JSON

In fact, mTOR-induced autophagy inhibition exacerbates the ultrastructural effects of METH [126,134–136], while rapamycin administration reverts both behavioral and morphological alterations induced by METH [137].

a(CHEBI:sirolimus) decreases act(a(CHEBI:methamphetamine)) View Subject | View Object

Appears in Networks:

bp(GO:autophagy) decreases act(a(CHEBI:methamphetamine)) View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) increases act(a(CHEBI:methamphetamine)) View Subject | View Object

Appears in Networks:

Evidence 07aab4f4cb
JSON

Likewise, rapamycin was found to be beneficial for ameliorating psychotic symptoms

a(CHEBI:sirolimus) decreases path(MESH:"Psychotic Disorders") View Subject | View Object

Appears in Networks:

Evidence 1ea18f8112
JSON

Noteworthy, genetic ablation of autophagy was shown to produce an extremely powerful DA release upon electrical stimuli, suggesting that autophagy is key to restrain DA release both upon basal neural activity and mostly after rapamycin-induced autophagy

a(CHEBI:sirolimus) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

bp(GO:autophagy) decreases sec(a(CHEBI:dopamine)) View Subject | View Object

Appears in Networks:

Evidence 4c02244934
JSON

In particular, CRMP2 is a cytosolic protein enriched in the CNS, which has been implicated in microtubule stabilization, and thus in the regulation of cytoskeletal dynamics and vesicle trafficking

a(GO:"microtubule cytoskeleton") association p(HGNC:DTNBP1) View Subject | View Object

Appears in Networks:

act(a(GO:cytoskeleton)) association p(HGNC:DTNBP1) View Subject | View Object

Appears in Networks:

bp(GO:"synaptic vesicle transport") association p(HGNC:DTNBP1) View Subject | View Object

Appears in Networks:

p(HGNC:DTNBP1) association a(GO:"microtubule cytoskeleton") View Subject | View Object

Appears in Networks:

p(HGNC:DTNBP1) association act(a(GO:cytoskeleton)) View Subject | View Object

Appears in Networks:

p(HGNC:DTNBP1) association bp(GO:"synaptic vesicle transport") View Subject | View Object

Appears in Networks:

Evidence 406336532b
JSON

This gene encodes for the DISC1 ubiquitous protein, which is implicated in neurogenesis, neuronal migration, axon/dendrite, and synapse formation

a(GO:dendrite) association p(HGNC:DISC1) View Subject | View Object

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a(GO:synapse) association p(HGNC:DISC1) View Subject | View Object

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bp(GO:"axon development") association p(HGNC:DISC1) View Subject | View Object

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bp(GO:"neuron migration") association p(HGNC:DISC1) View Subject | View Object

Appears in Networks:

bp(MESH:Neurogenesis) association p(HGNC:DISC1) View Subject | View Object

Appears in Networks:

p(HGNC:DISC1) association bp(MESH:Neurogenesis) View Subject | View Object

Appears in Networks:

p(HGNC:DISC1) association bp(GO:"neuron migration") View Subject | View Object

Appears in Networks:

p(HGNC:DISC1) association bp(GO:"axon development") View Subject | View Object

Appears in Networks:

p(HGNC:DISC1) association a(GO:dendrite) View Subject | View Object

Appears in Networks:

p(HGNC:DISC1) association a(GO:synapse) View Subject | View Object

Appears in Networks:

Evidence 9dabf84fb6
JSON

The biological implication behind an impairment of microtubule dynamics is confirmed in post-mortem schizophrenic brain samples, as well as in mouse models of schizophrenia, where mTOR-dependent autophagy dysfunction is accompanied by an altered gene expression and protein levels of the microtubule-associated protein 6 (MAP6)

act(a(GO:microtubule)) negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Schizophrenia

p(HGNC:MAP6) association act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Schizophrenia

p(HGNC:MTOR) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Schizophrenia

act(p(HGNC:MTOR)) association p(HGNC:MAP6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Schizophrenia

path(MESH:Schizophrenia) negativeCorrelation act(a(GO:microtubule)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Schizophrenia

Evidence e3e289495c
JSON

In schizophrenia, a progressive synaptic disorder is likely to promote neurodegeneration

act(a(GO:synapse)) association path(HBP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Schizophrenia

path(HBP:Neurodegeneration) association act(a(GO:synapse)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Schizophrenia

Evidence 0170523f87
JSON

On the other hand, chronic treatment with an eight-amino-acid peptide snippet from ADNP (NAP), also known as davunetide, restored both Beclin1 and ADNP mRNA levels along with ADNP-LC3 interaction, thus providing neuroprotection while ameliorating schizophrenic-like behavioral and cognitive deficits in Map6+/- mice

a(PUBCHEM:9832404) increases complex(p(HGNC:ADNP), p(HGNC:MAP1LC3A)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Schizophrenia

a(PUBCHEM:9832404) increases r(HGNC:BECN1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Schizophrenia

a(PUBCHEM:9832404) increases r(HGNC:ADNP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Schizophrenia

a(PUBCHEM:9832404) decreases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Schizophrenia

a(PUBCHEM:9832404) increases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Schizophrenia

a(PUBCHEM:9832404) decreases path(MESH:"Mental Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Schizophrenia

Evidence 6527f07b5c
JSON

This gene is located on chromosome 8p21 and it encodes the cytosolic microtubule-associated protein CRMP2 (collapsin response mediator protein-2), which is highly expressed in the CNS and plays a role in axonal growth

bp(GO:"axon development") association p(HGNC:DPYSL2) View Subject | View Object

Appears in Networks:

p(HGNC:DPYSL2) association bp(GO:"axon development") View Subject | View Object

Appears in Networks:

g(HGNC:DPYSL2) increases p(HGNC:DPYSL2) View Subject | View Object

Appears in Networks:

Evidence 06b1507c52
JSON

In addition, cytoskeletal derangement appears as a prominent feature of the ultrastructural pathology of schizophrenia

bp(GO:"cytoskeleton organization") negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) negativeCorrelation bp(GO:"cytoskeleton organization") View Subject | View Object

Appears in Networks:

Evidence f73e8737e5
JSON

Alterations in MAP2 immunoreactivity within the subiculum, entorhinal cortex, hippocampus, and prefrontal cortex have been suggested as the primary array of cytoskeletal abnormalities, which in turn result in impaired neurotransmission observed in schizophrenia

bp(GO:"cytoskeleton organization") increases bp(GO:"neuron-neuron synaptic transmission") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Entorhinal Cortex
MeSH
Hippocampus
MeSH
Prefrontal Cortex

bp(GO:"neuron-neuron synaptic transmission") negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Entorhinal Cortex
MeSH
Hippocampus
MeSH
Prefrontal Cortex

p(HGNC:MAP2) increases bp(GO:"cytoskeleton organization") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Entorhinal Cortex
MeSH
Hippocampus
MeSH
Prefrontal Cortex

path(MESH:Schizophrenia) negativeCorrelation bp(GO:"neuron-neuron synaptic transmission") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Entorhinal Cortex
MeSH
Hippocampus
MeSH
Prefrontal Cortex

Evidence a6239bfb59
JSON

Remarkably, the marked reduction of p35 levels in schizophrenic brains, which mirrors enhanced CDK5 activity [247], suggests a role for CDK5-CRMP2-dependent alterations of cytoskeleton architecture and psychiatric behavior

bp(GO:"cytoskeleton organization") association complex(p(HGNC:CDK5), p(HGNC:DPYSL2)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

act(p(HGNC:CDK5)) positiveCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

act(p(HGNC:CDK5)) negativeCorrelation p(HGNC:CDK5R1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

p(HGNC:CDK5R1) negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

p(HGNC:CDK5R1) negativeCorrelation act(p(HGNC:CDK5)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

complex(p(HGNC:CDK5), p(HGNC:DPYSL2)) association bp(GO:"cytoskeleton organization") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

complex(p(HGNC:CDK5), p(HGNC:DPYSL2)) association path(MESH:"Mental Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Mental Disorders") association complex(p(HGNC:CDK5), p(HGNC:DPYSL2)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:Schizophrenia) negativeCorrelation p(HGNC:CDK5R1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:Schizophrenia) positiveCorrelation act(p(HGNC:CDK5)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence c3578b82df
JSON

Remarkably, DISC1 plays a key role in DA neurotransmission

bp(GO:"dopamine secretion, neurotransmission") association p(HGNC:DISC1) View Subject | View Object

Appears in Networks:

p(HGNC:DISC1) association bp(GO:"dopamine secretion, neurotransmission") View Subject | View Object

Appears in Networks:

Evidence baaa20c5d8
JSON

Cytoskeleton organization and dynamics depend on the fine control of microtubule assembly, which relies on the interaction of microtubules with a specific class of proteins known as microtubule-associated protein (MAP).

bp(GO:"microtubule polymerization") increases bp(GO:"cytoskeleton organization") View Subject | View Object

Appears in Networks:

complex(a(GO:microtubule), a(MESH:"Microtubule-Associated Proteins")) increases bp(GO:"microtubule polymerization") View Subject | View Object

Appears in Networks:

Evidence 7a5e8479e1
JSON

Again, an impaired Akt signaling, achieved by neuronal deletion of rictor, a key regulatory subunit of mTORC2, contributes to schizophrenia-like phenotypes in rictor-null (KO) mice

bp(GO:"protein kinase B signaling") association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

p(MGI:Rictor) decreases bp(GO:"protein kinase B signaling") View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association bp(GO:"protein kinase B signaling") View Subject | View Object

Appears in Networks:

Evidence 632705c7e9
JSON

Moreover, it has been demonstrated that NRG1 also regulates DISC1 expression [230], thus further worsening the aberrancy of the Akt–mTOR pathway and the pathogenesis of schizophrenia and related behaviors.

bp(GO:"protein kinase B signaling") association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

bp(GO:"protein kinase B signaling") association p(HGNC:NRG1) View Subject | View Object

Appears in Networks:

p(HGNC:NRG1) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

p(HGNC:NRG1) regulates p(HGNC:DISC1) View Subject | View Object

Appears in Networks:

p(HGNC:NRG1) association bp(GO:"protein kinase B signaling") View Subject | View Object

Appears in Networks:

p(HGNC:NRG1) association act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) association p(HGNC:NRG1) View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association bp(GO:"protein kinase B signaling") View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association p(HGNC:NRG1) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

Evidence 21e544c7e7
JSON

Remarkably, further investigation on the autophagy pathway revealed that all these misfolded proteins are autophagy substrates depending on mTOR activity

bp(GO:autophagy) increases deg(p(MESH:Proteins, pmod(HBP:misfolded))) View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) regulates deg(p(MESH:Proteins, pmod(HBP:misfolded))) View Subject | View Object

Appears in Networks:

Evidence a1a873a967
JSON

Therefore, a common pathogenesis underlying all these NDDs disorders has been linked to autophagy inhibition due to mTOR hyperactivation

bp(GO:autophagy) decreases path(MESH:"Neurodegenerative Diseases") View Subject | View Object

Appears in Networks:

bp(GO:autophagy) negativeCorrelation act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) negativeCorrelation bp(GO:autophagy) View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) positiveCorrelation path(MESH:"Neurodegenerative Diseases") View Subject | View Object

Appears in Networks:

path(MESH:"Neurodegenerative Diseases") positiveCorrelation act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

Evidence c392ae39bd
JSON

The relevance of autophagy for sustaining these mTOR-induced effects is confirmed by drugs inducing autophagy independently of mTOR activation

bp(GO:autophagy) regulates act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

Evidence ea8d6b2e00
JSON

This confirms our previous studies showing that both genetic and pharmacological autophagy inhibition worsen the effects of METH administration

bp(GO:autophagy) decreases act(a(CHEBI:methamphetamine)) View Subject | View Object

Appears in Networks:

Evidence 1c65296101
JSON

Remarkably, the identification of rare genetic variants of ULK1 in a cohort of schizophrenic patients by means of exome sequence analysis strengthens the idea of a key role of both disrupted mTOR signaling and autophagy in the pathophysiology and susceptibility to schizophrenia

bp(GO:autophagy) negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

p(HGNC:ULK1, var("?")) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) negativeCorrelation act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association p(HGNC:ULK1, var("?")) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) negativeCorrelation bp(GO:autophagy) View Subject | View Object

Appears in Networks:

Evidence 2c7059f9e4
JSON

A few months later, another transcriptomic study reported a BA 22-specific down-regulation in several autophagy-related genes, thus strengthening the link between impaired autophagy and schizophrenia positive symptoms

bp(GO:autophagy) negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

bp(GO:autophagy) negativeCorrelation path(MESH:Hallucinations) View Subject | View Object

Appears in Networks:

path(MESH:Hallucinations) negativeCorrelation bp(GO:autophagy) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) negativeCorrelation bp(GO:autophagy) View Subject | View Object

Appears in Networks:

Evidence a3392bebd8
JSON

Later on, further analysis reported a disruption of the autophagy pathway also in the hippocampus of post-mortem schizophrenic patients

bp(GO:autophagy) negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

path(MESH:Schizophrenia) negativeCorrelation bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence fac833071f
JSON

In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls

bp(GO:autophagy) association p(HGNC:BECN1) View Subject | View Object

Appears in Networks:

bp(GO:autophagy) association p(HGNC:ULK2) View Subject | View Object

Appears in Networks:

bp(GO:autophagy) association p(HGNC:ATG3) View Subject | View Object

Appears in Networks:

p(HGNC:ATG3) association bp(GO:autophagy) View Subject | View Object

Appears in Networks:

p(HGNC:BECN1) association bp(GO:autophagy) View Subject | View Object

Appears in Networks:

p(HGNC:ULK2) association bp(GO:autophagy) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) decreases p(HGNC:BECN1) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) decreases p(HGNC:ULK2) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) decreases p(HGNC:ATG3) View Subject | View Object

Appears in Networks:

Evidence a23344d9ff
JSON

Preliminary in vitro studies demonstrated that two proteins, namely DISC1 and dysbindin-1, which are encoded by two susceptibility genes for schizophrenia, can form insoluble protein aggregates that are reminiscent of those occurring in neurodegenerative disorders

p(HGNC:DISC1) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

p(HGNC:DISC1) increases a(HBP:"protein aggregates") View Subject | View Object

Appears in Networks:

p(HGNC:DTNBP1) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

p(HGNC:DTNBP1) increases a(HBP:"protein aggregates") View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association p(HGNC:DISC1) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association p(HGNC:DTNBP1) View Subject | View Object

Appears in Networks:

Evidence 51d656d6b1
JSON

Intriguingly, the interactome analysis of both DISC1, dysbindin-1, and CRMP2, which is another susceptibility gene for schizophrenia, revealed common protein interactions with microtubules, actin cytoskeleton, and proteins involved in intracellular transport

p(HGNC:DISC1) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

p(HGNC:DPYSL2) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

p(HGNC:DTNBP1) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association p(HGNC:DISC1) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association p(HGNC:DTNBP1) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association p(HGNC:DPYSL2) View Subject | View Object

Appears in Networks:

Evidence 4cdb152bb0
JSON

In particular, DISC1 acts by blocking KIAA1212, an Akt-binding partner, which directly interacts with Akt and strengthens the activation of this kinase, which represents a major mediator of the mTOR pathway.

p(HGNC:DISC1) decreases act(p(HGNC:CCDC88A)) View Subject | View Object

Appears in Networks:

complex(p(FPLX:AKT), p(HGNC:CCDC88A)) increases act(p(FPLX:AKT)) View Subject | View Object

Appears in Networks:

p(FPLX:AKT) regulates act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

Evidence 1ff77b9fe1
JSON

In line with this, the dendritic spine-regulating activity of CRMP2 is under the control of the cyclin-dependent kinase 5 (CDK5)

p(HGNC:DPYSL2) regulates a(GO:"dendritic spine") View Subject | View Object

Appears in Networks:

p(HGNC:CDK5) regulates p(HGNC:DPYSL2) View Subject | View Object

Appears in Networks:

Evidence b6942397da
JSON

Therefore, the binding between DISC1 and KIAA1212 prevents KIAA1212-dependent Akt activation (Figure 3).

p(HGNC:CCDC88A) increases act(p(FPLX:AKT)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:CCDC88A), p(HGNC:DISC1)) decreases act(p(FPLX:AKT)) View Subject | View Object

Appears in Networks:

Evidence c9a8f02969
JSON

The binding between ErbB4 and PI3K activates this latter kinase, which in turn can phosphorylate and activate its downstream target Akt

complex(p(FPLX:PI3K), p(HGNC:ERBB4)) increases act(p(FPLX:PI3K)) View Subject | View Object

Appears in Networks:

act(p(FPLX:PI3K), ma(kin)) increases p(FPLX:AKT, pmod(Ph)) View Subject | View Object

Appears in Networks:

act(p(FPLX:PI3K)) increases act(p(FPLX:AKT)) View Subject | View Object

Appears in Networks:

Evidence 6c6436a474
JSON

Furthermore, genetic linkage and association studies led to the identification of two additional susceptibility factors related to schizophrenia, such as neuregulin-1 (NRG1) and its receptor ErbB4

p(HGNC:ERBB4) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

p(HGNC:NRG1) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association p(HGNC:NRG1) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) association p(HGNC:ERBB4) View Subject | View Object

Appears in Networks:

Evidence ed81fd8a9d
JSON

ADNP is an essential protein for brain development and it has been shown to physically interact with a key protein in autophagosome biogenesis and maturation, namely LC3

p(HGNC:ADNP) increases bp(GO:"brain development") View Subject | View Object

Appears in Networks:

p(HGNC:MAP1LC3A) increases bp(GO:"autophagosome assembly") View Subject | View Object

Appears in Networks:

p(HGNC:MAP1LC3A) increases bp(GO:"autophagosome maturation") View Subject | View Object

Appears in Networks:

Evidence c9e64c5cca
JSON

This decreases Akt activity, which in turn dampens mTOR signaling

complex(p(HGNC:CCDC88A), p(HGNC:DISC1)) decreases act(p(FPLX:AKT)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:CCDC88A), p(HGNC:DISC1)) decreases act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

Evidence 0f505a01ea
JSON

In particular, NRG1, which is mostly involved in regulating neurodevelopment and neurotransmission, acts by binding ErbB4, a type I transmembrane receptor tyrosine kinase belonging to the family of ErbB proteins, which contain a binding site for PI3K kinase, an AKT upstream effector, in the C-terminal cytoplasmic tail (CYT)

complex(p(HGNC:ERBB4), p(HGNC:NRG1)) regulates bp(GO:"generation of neurons") View Subject | View Object

Appears in Networks:

complex(p(HGNC:ERBB4), p(HGNC:NRG1)) regulates bp(GO:"neuron-neuron synaptic transmission") View Subject | View Object

Appears in Networks:

Evidence 02da67aded
JSON

Noteworthy, NRG1/ErbB4 signaling plays a key role in DA-related behaviors by increasing DA release within the hippocampus, striatum, and prefrontal cortex

act(complex(p(HGNC:ERBB4), p(HGNC:NRG1))) increases sec(a(CHEBI:dopamine)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Corpus Striatum
MeSH
Hippocampus
MeSH
Prefrontal Cortex

Evidence e756b731aa
JSON

This is the case of the disrupted in schizophrenia 1 (DISC1) gene, a schizophrenia-related gene, originally discovered in a large Scottish family with a high incidence of psychiatric symptoms

g(HGNC:DISC1) association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Schizophrenia) association g(HGNC:DISC1) View Subject | View Object

Appears in Networks:

Evidence bad164171e
JSON

Another identified susceptibility gene for schizophrenia is the dihydropyrimidinase-like 2 (DPYSL2) gene

g(HGNC:DPYSL2) association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Schizophrenia) association g(HGNC:DPYSL2) View Subject | View Object

Appears in Networks:

Evidence 6049f7150a
JSON

In detail, the activation of CDK5 by D1R occurs via proteolysis of p35, the binding partner of CDK5

p(HGNC:CDK5R1, frag("?")) increases act(p(HGNC:CDK5)) View Subject | View Object

Appears in Networks:

p(HGNC:DRD1) increases p(HGNC:CDK5) View Subject | View Object

Appears in Networks:

Evidence 6fab3a2b38
JSON

In addition, these findings strongly suggest that DISC1 alterations may increase the risk of schizophrenia by dysregulating DA release

p(HGNC:DISC1, var("?")) increases path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

p(HGNC:DISC1, var("?")) decreases sec(a(CHEBI:dopamine)) View Subject | View Object

Appears in Networks:

Evidence 5bf647b6ac
JSON

Therefore, disruption of DISC1 activity, due to genetic rearrangements (i.e., balanced (1;11) (q42;q14) chromosomal translocation) or missense mutations, produces schizophrenic-like behavior, which is bound to enhanced Akt activity, over-activation of mTOR signaling, and depressed autophagy

p(HGNC:DISC1, var("?")) increases path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

p(HGNC:DISC1, var("?")) increases act(p(FPLX:AKT)) View Subject | View Object

Appears in Networks:

p(HGNC:DISC1, var("?")) increases act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

p(HGNC:DISC1, var("?")) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

Evidence 10e76c6f9f
JSON

Increased activity of D1R is considered as a major determinant of neuropsychiatric alterations occurring in both METH models/abusers and in schizophrenia

act(p(HGNC:DRD1)) positiveCorrelation path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Schizophrenia) positiveCorrelation act(p(HGNC:DRD1)) View Subject | View Object

Appears in Networks:

Evidence 836ef1ed77
JSON

This is key, because abnormal stimulation of D1R and subsequent signaling cascades were recently shown to produce an over-activation of mTOR and inhibition of the autophagy machinery

act(p(HGNC:DRD1)) increases act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

act(p(HGNC:DRD1)) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

Evidence b1dcaad30f
JSON

Among various identified MAPs, microtubule-associated protein 2 (MAP2), which belongs to the MAP2/Tau family, is enriched in the brain and especially in dendrites, where it contributes to microtubule stabilization and overall dendritic architecture.

p(HGNC:MAP2) increases a(GO:microtubule) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Dendrites

p(HGNC:MAP2) increases bp(GO:"dendritic spine organization") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Dendrites

Evidence ba5e7a846b
JSON

Moreover, pathological deposition of hyperphosphorylated MAP-tau (MAPT), which is the hallmark of several neurodegenerative disorders such as AD and frontotemporal dementia (FTD), has been described in elderly subjects with schizophrenia

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Frontotemporal Dementia") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:

path(MESH:"Frontotemporal Dementia") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:

Evidence afced2ba33
JSON

For instance, an increased mTOR activity correlates with accumulation of Abeta and hyperphosphorylated tau in AD brains

act(p(HGNC:MTOR)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

act(p(HGNC:MTOR)) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

Evidence f40cf8a8d5
JSON

On the other hand, some evidence indicates that suppressing mTOR activity ameliorates AD cognitive defects by decreasing Abeta and tau pathology

act(p(HGNC:MTOR)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) increases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:

act(p(HGNC:MTOR)) decreases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 16051e80de
JSON

In addition, the occurrence of alpha synuclein gene (SNCA) polymorphisms is associated with human METH psychosis [166].

p(HGNC:SNCA, var("?")) association path(MESH:"Psychotic Disorders") View Subject | View Object

Appears in Networks:

path(MESH:"Psychotic Disorders") association p(HGNC:SNCA, var("?")) View Subject | View Object

Appears in Networks:

path(MESH:Schizophrenia) increases path(MESH:"Psychotic Disorders") View Subject | View Object

Appears in Networks:

Evidence 1f9c310843
JSON

Remarkably, a very recent neuropathological examination provided evidence for TDP-43-positive cytosolic inclusions and dystrophic neurites in the brain of a patient diagnosed with FTLD presenting brief psychotic episodes and catatonia, which is a syndrome related to schizophrenia

p(HGNC:TARDBP, loc(GO:"inclusion body")) association path(MESH:"Frontotemporal Lobar Degeneration") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

p(HGNC:TARDBP, loc(HBP:"dystrophic neurite")) association path(MESH:"Frontotemporal Lobar Degeneration") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Frontotemporal Lobar Degeneration") association path(MESH:"Psychotic Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Frontotemporal Lobar Degeneration") association path(MESH:Catatonia) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Frontotemporal Lobar Degeneration") association p(HGNC:TARDBP, loc(GO:"inclusion body")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Frontotemporal Lobar Degeneration") association p(HGNC:TARDBP, loc(HBP:"dystrophic neurite")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Psychotic Disorders") association path(MESH:"Frontotemporal Lobar Degeneration") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:Catatonia) association path(MESH:"Frontotemporal Lobar Degeneration") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:Catatonia) association path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:Schizophrenia) association path(MESH:Catatonia) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence f66fbe2f04
JSON

Likewise, the psychostimulant effects experienced by METH-addicted patients rely on increased DA synthesis and massive DA release from nerve terminals within limbic areas as occurring in the schizophrenic brain

path(MESH:Schizophrenia) increases a(CHEBI:dopamine) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:Schizophrenia) increases tloc(a(CHEBI:dopamine), fromLoc(MESH:"Nerve Endings"), toLoc(MESH:"Limbic System")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence 38fbe67dff
JSON

Notably, a marked reduction in MAP2 immunoreactivity, along with a decrease in dendritic arbor, is reported in the primary auditory cortex (BA41) of schizophrenic subjects compared with healthy controls

path(MESH:Schizophrenia) decreases p(HGNC:MAP2) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Auditory Cortex

path(MESH:Schizophrenia) decreases a(GO:dendrite) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Auditory Cortex

Evidence 07f0fc0615
JSON

Momeni and colleagues (2010) recently reported two relatives with an early age at onset (27 and 29 years) of schizophrenic symptoms showing a marked neuronal tau deposition, as confirmed at pathological examination

path(MESH:Schizophrenia) increases p(HGNC:MAPT, loc(MESH:Neurons)) View Subject | View Object

Appears in Networks:

Evidence c420e3e8b9
JSON

Notably, post-mortem analysis performed in the prefrontal cortex of schizophrenic patients revealed oligodendrocyte ultrastructural abnormalities

path(MESH:Schizophrenia) decreases bp(GO:"oligodendrocyte development") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Prefrontal Cortex

Evidence dfac935405
JSON

Dysregulation in Akt signaling and altered Akt protein levels were found in the frontal cortex and hippocampus of post-mortem brain samples from individuals affected by schizophrenia

path(MESH:Schizophrenia) decreases bp(GO:"protein kinase B signaling") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Prefrontal Cortex

path(MESH:Schizophrenia) decreases p(FPLX:AKT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Prefrontal Cortex

Evidence ea77dd3420
JSON

In detail, the analysis of mRNA expression of a key protein for autophagy initiation, namely beclin1, revealed a significant region-specific reduction in hippocampal samples from 12 schizophrenic patients compared with 12 age-matched healthy controls.

path(MESH:Schizophrenia) decreases p(HGNC:BECN1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence bd4ab60aea
JSON

Immuno-histochemical analysis showed a three-fold decrease in the number of beclin1-positive cells in Map6+/- mice

path(MESH:Schizophrenia) decreases p(HGNC:BECN1) View Subject | View Object

Appears in Networks:

Evidence 5c197c008e
JSON

A reduction of ADNP and its homologous protein, ADNP2, is observed in schizophrenic patients [254], and it is recapitulated in Map6-deficient (Map6+/-) mice, another transgenic model of schizophrenia

path(MESH:Schizophrenia) decreases p(HGNC:ADNP) View Subject | View Object

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path(MESH:Schizophrenia) decreases p(HGNC:ADNP2) View Subject | View Object

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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.