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a(HBP:HBP00093)

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Entity

Name
HBP00093
Namespace
HBP
Namespace Version
20181029
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/785431732a26d6809b4162d98b95687d16404e63/export/hbp.belns

Appears in Networks 2

Alpha-synuclein oligomers: a new hope v1.0.0

Structural and functional properties of prefibrillar α-synuclein oligomers v1.0.0

In-Edges 11

a(CHEBI:salubrinal) decreases a(HBP:HBP00093) View Subject | View Object

furthermore, treatment with salubrinal, which alleviates ER stress, reduced oligomeric accumulation in the ER. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High
MeSH
Endoplasmic Reticulum

a(MESH:Astrocytes) increases deg(a(HBP:HBP00093)) View Subject | View Object

Interestingly, it was very recently reported that astrocytes take up a-syn oligomers and degrade it via the lysosomal pathway, but this pathway can become saturated leading to mitochondrial fragmentation [89]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High

bp(GO:autophagy) increases a(HBP:HBP00093) View Subject | View Object

a-syn accumulation has been linked to autophagic and lysosomal dysfunction, which may in turn lead to a-syn aggregation and production of more detrimental oligomers. PubMed:28803412

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

complex(a(HBP:HBP00093), p(HGNC:VAMP1)) hasComponent a(HBP:HBP00093) View Subject | View Object

Appears in Networks:

p(HGNC:HDAC6) decreases a(HBP:HBP00093) View Subject | View Object

Finally, inhibition of histone deacetylase 6 (HDAC6), which was previously shown to be involved in the response to cytotoxic ubiquitinated aggregates, increased the oligomeric content in vitro, while overexpression of HDAC6 produced the opposite effect [36]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High
MeSH
Endoplasmic Reticulum

path(MESH:"Parkinson Disease") positiveCorrelation a(HBP:HBP00093) View Subject | View Object

Elevated levels of a-syn oligomers were found in PD patients compared to controls or AD patients in brain homogenate, CSF and serum. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Cerebrospinal Fluid
MeSH
Serum

p(HGNC:TFEB) decreases a(HBP:HBP00093) View Subject | View Object

Accordingly, overexpression of transcription factor EB (TFEB) was shown to correct lysosomal defects induced by the viral overexpression of a-syn and to downregulate the accumulation of oligomers in vivo [32]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

a(CHEBI:dopamine) increases a(HBP:HBP00093) View Subject | View Object

The neurotransmitter dopamine (DA) has been shown to promote the formation of stable, SDS-resistant α -syn oligomers both in vitro and in neurons30–32 by different mechanisms, including the formation of stable α -syn-DA-quinone adducts, methionine oxidation, or non-covalent interactions33. PubMed:27075649

Appears in Networks:
Annotations
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Lewy Bodies

a(CHEBI:dopamine) increases a(HBP:HBP00093) View Subject | View Object

DA-mediated α -syn oligomers constitute a range of SDS-resistant species with apparent molecular weights ranging from over 2200 to 200 kDa as determined by SEC (Fig. 4a). PubMed:27075649

Appears in Networks:
Annotations
MeSH
Intracellular Space
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Lewy Bodies

a(CHEBI:glutaraldehyde) increases a(HBP:HBP00093) View Subject | View Object

GA-cross-linked α -syn oligomers are also a heterogeneous set of SDS-resistant oligomeric species (Fig. 4b). PubMed:27075649

Appears in Networks:
Annotations
MeSH
Intracellular Space
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Lewy Bodies

a(HBP:HBP00092) negativeCorrelation a(HBP:HBP00093) View Subject | View Object

Increasing amounts of fibrils and a concomitant decrease in the amount of oligomeric species were observed upon longer incubation times (Supplementary Fig. S1). PubMed:27075649

Appears in Networks:
Annotations
MeSH
Intracellular Space
Cell Ontology (CL)
neuron
Confidence
Medium
MeSH
Lewy Bodies

Out-Edges 23

a(HBP:HBP00093) increases path(MESH:"Parkinson Disease") View Subject | View Object

. Multiple lines of evidence now suggest that oligomeric species of a-syn, which are thought to precede the fibrillar aggregates found in Lewy bodies, are the culprits for neuronal degeneration in Parkinson’s disease PubMed:28803412

Appears in Networks:
Annotations
Confidence
Medium

a(HBP:HBP00093) biomarkerFor path(MESH:"Parkinson Disease") View Subject | View Object

Oligomeric detection may have uses as a diagnostic biomarker, as a biomarker of the progression of the disease, and in the future, perhaps as an index of response to novel therapies. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

a(HBP:HBP00093) positiveCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

Elevated levels of a-syn oligomers were found in PD patients compared to controls or AD patients in brain homogenate, CSF and serum. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Cerebrospinal Fluid
MeSH
Serum

a(HBP:HBP00093) increases a(HBP:HBP00092) View Subject | View Object

. Multiple lines of evidence now suggest that oligomeric species of a-syn, which are thought to precede the fibrillar aggregates found in Lewy bodies, are the culprits for neuronal degeneration in Parkinson’s disease PubMed:28803412

Appears in Networks:
Annotations
Confidence
Medium

a(HBP:HBP00093) increases bp(GO:"apoptotic process") View Subject | View Object

In vitro formed a-syn oligomers ectopically applied to cell cultures or formed due to overexpression of a-syn induce cell death [20, 30, 109, 149], which has been recapitulated in vivo in several studies. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High

a(HBP:HBP00093) increases bp(GO:"apoptotic process") View Subject | View Object

In contrast, a-syn 30–110 that forms fibrils at a fast rate, did not display toxicity, indicating that oligomers are indeed the toxic species leading to TH-neuron loss in vivo [162]. PubMed:28803412

Appears in Networks:
Annotations
Cell Ontology (CL)
neuron
Confidence
High

a(HBP:HBP00093) decreases a(MESH:Mitochondria) View Subject | View Object

In 2014 Plotegher et al. showed that mitochondrial morphology is disrupted by a-syn oligomers, which cause fragmentation of these organelles in vitro in SH-SY5Y cells [124]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High

a(HBP:HBP00093) increases bp(HBP:HBP00037) View Subject | View Object

All these results show that a-syn oligomers are implicated in mitochondrial dysfunction across different models. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High

a(HBP:HBP00093) increases bp(MESH:"Endoplasmic Reticulum Stress") View Subject | View Object

Accumulation of oligomers has been demonstrated in a transgenic mouse overexpressing A53T a-syn and in Parkinson’s disease brain tissue, resulting in chronic ER stress and impaired ER protein quality control [25]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High

a(HBP:HBP00093) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

This can be inhibited by a-syn oligomers: oligomers were shown to inhibit proteasomal activity, which was blocked by addition of antibodies that neutralized the interaction [87]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Endoplasmic Reticulum

a(HBP:HBP00093) increases bp(GO:"microglial cell activation") View Subject | View Object

However, in a different report, oligomers were shown to activate proinflammatory signals in microglial cells in vitro and in vivo, and this was prevented by addition of a MAP kinase inhibitor [161]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

a(HBP:HBP00093) increases bp(GO:"inflammatory response") View Subject | View Object

Kim et al. demonstrated that a-syn oligomers lead to microglial inflammatory responses via TLR2 activation [74]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

a(HBP:HBP00093) increases act(p(HGNC:TLR2)) View Subject | View Object

Kim et al. demonstrated that a-syn oligomers lead to microglial inflammatory responses via TLR2 activation [74]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

a(HBP:HBP00093) increases a(CHEBI:"reactive oxygen species") View Subject | View Object

Another report by Zhang and collaborators also highlighted glial activation and production of reactive oxygen species in response to oligomer-like preparations of aggregated a-syn [168]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

a(HBP:HBP00093) decreases a(MESH:"Cell Membrane") View Subject | View Object

A-syn oligomers can stabilize membrane defects accelerating membrane damage [19] and can alter membrane properties such as input resistance reducing neuronal excitability [72] PubMed:28803412

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

a(HBP:HBP00093) increases tloc(a(CHEBI:"calcium(2+)"), fromLoc(GO:"extracellular space"), toLoc(GO:"intracellular part")) View Subject | View Object

Dysfunctional membranes can also have an important impact on calcium homeostasis; some types of oligomers can lead to a cytotoxic calcium influx presumably by building pore-like structures [30]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

a(HBP:HBP00093) decreases bp(GO:"synaptic vesicle transport") View Subject | View Object

The trafficking of synaptic vesicles may also be negatively impacted by a-syn oligomers, which have been shown to decrease axonal transport by decreasing microtubule stability and impairing the interaction between kinesin and microtubules [128], as well as inhibiting tubulin polymerisation [20]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

a(HBP:HBP00093) decreases bp(GO:"axonal transport") View Subject | View Object

The trafficking of synaptic vesicles may also be negatively impacted by a-syn oligomers, which have been shown to decrease axonal transport by decreasing microtubule stability and impairing the interaction between kinesin and microtubules [128], as well as inhibiting tubulin polymerisation [20]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

a(HBP:HBP00093) decreases complex(a(GO:microtubule), a(MESH:Kinesin)) View Subject | View Object

The trafficking of synaptic vesicles may also be negatively impacted by a-syn oligomers, which have been shown to decrease axonal transport by decreasing microtubule stability and impairing the interaction between kinesin and microtubules [128], as well as inhibiting tubulin polymerisation [20]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

a(HBP:HBP00093) decreases a(MESH:"Golgi Apparatus") View Subject | View Object

Golgi fragmentation has also been observed as a result of oligomers formed by over-expression of a-syn in COS-7 cells [55]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

a(HBP:HBP00093) increases a(CHEBI:"calcium(2+)") View Subject | View Object

1 nM (Fig. 3a, right panels and Fig. 3b, red curve, solid line) and 0.2 nM α -syn fibrils (Fig. 3b, red curve, dashed line) induced a progressive and significant increase of intracellular Ca2+ levels, as revealed by the rise of Fluo-4 fluorescence in exposed SH-SY5Y cells. In contrast, only a modest Ca2+ increase was observed in cells exposed to 300 nM on-fibrillar assembly pathway oligomeric α -syn (Fig. 3a, middle panels and Fig. 3b, blue curve, solid line) or 10 μM monomeric α -syn (Fig. 3a, left panels and Fig. 3b, black curve, solid line). PubMed:27075649

Appears in Networks:
Annotations
MeSH
Intracellular Space
Cell Ontology (CL)
neuron
Confidence
Medium
MeSH
Lewy Bodies

a(HBP:HBP00093) increases bp(GO:"apoptotic process") View Subject | View Object

α -syn fibrils revealed to be highly toxic to cells at all the concentrations we tested, spanning 1 to 0.01 nM (53.4 ± 4% inhibition of MTT reduction at 0.01 nM, i.e. 0.1 μM equivalent monomer concentration) whereas α -syn oligomers only slightly impaired cell viability (23.9 ± 6% inhibition of MTT reduction at 300 nM, i.e. 10 μM initial monomer concentration) (Fig. 3c). PubMed:27075649

Appears in Networks:
Annotations
MeSH
Intracellular Space
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Lewy Bodies

a(HBP:HBP00093) negativeCorrelation a(HBP:HBP00092) View Subject | View Object

Increasing amounts of fibrils and a concomitant decrease in the amount of oligomeric species were observed upon longer incubation times (Supplementary Fig. S1). PubMed:27075649

Appears in Networks:
Annotations
MeSH
Intracellular Space
Cell Ontology (CL)
neuron
Confidence
Medium
MeSH
Lewy Bodies

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

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.