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PubMed: 28803412

Title
Alpha-synuclein oligomers: a new hope.
Journal
Acta neuropathologica
Volume
134
Issue
None
Pages
819-838
Date
2017-12-01
Authors
Roberts RF | Bengoa-Vergniory N | Alegre-Abarrategui J | Wade-Martins R

Evidence 5a070b4318
JSON

Epigallocatechin-3-gallate (EGCG), a small molecule that been shown to inhibit the aggregation of several amyloidogenic proteins such as a-syn, amyloid-beta and huntingtin [9, 37, 38, 105] binds to unfolded native amyloid-beta and a-syn and promotes the formation of nontoxic oligomers that do not convert into amyloid fibrils [37].

a(CHEBI:"(-)-epigallocatechin 3-gallate") decreases a(HBP:HBP00016) View Subject | View Object

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

a(CHEBI:"(-)-epigallocatechin 3-gallate") decreases a(HBP:HBP00018) View Subject | View Object

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

a(CHEBI:"(-)-epigallocatechin 3-gallate") decreases a(HBP:HBP00017) View Subject | View Object

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

Evidence fc7566cf97
JSON

In vitro studies have shown that curcumin inhibited the formation of fibrils and disaggregated amyloid-beta and a-syn [112, 114, 155].

a(CHEBI:curcumin) decreases a(HBP:HBP00092) View Subject | View Object

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

a(CHEBI:curcumin) decreases a(HBP:HBP00016) View Subject | View Object

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

a(CHEBI:curcumin) decreases a(HBP:HBP00018) View Subject | View Object

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

Evidence 525aaf1063
JSON

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

a(CHEBI:salubrinal) decreases bp(MESH:"Endoplasmic Reticulum Stress") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

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

Appears in Networks:
Annotations
Confidence
High
MeSH
Endoplasmic Reticulum

Evidence 3e69242d60
JSON

Not only did this discovery draw attention to aggregated forms of a-syn as mediators of Parkinson’s disease pathogenesis, but also opened the door to the use of a-syn detection techniques for diagnosis and staging.

a(HBP:HBP00016) increases path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 4954b700f0
JSON

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].

a(HBP:HBP00092) causesNoChange bp(GO:"apoptotic process") View Subject | View Object

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

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

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

Evidence ac786fb8ff
JSON

a report by Hoffmann et al. showed that fibrillar a-syn induced a more pronounced inflammatory response in microglial cells [61].

a(HBP:HBP00092) increases bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

a(HBP:HBP00092) increases bp(GO:"microglial cell activation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

Evidence fe3357ee22
JSON

. 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

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

Appears in Networks:
Annotations
Confidence
Medium

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

Appears in Networks:
Annotations
Confidence
Medium

Evidence 39f93b9837
JSON

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.

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

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence abfc9d70ba
JSON

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

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

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

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

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

Evidence 117728b803
JSON

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.

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

Appears in Networks:
Annotations
Confidence
High

Evidence 3fab2edf34
JSON

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].

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

Appears in Networks:
Annotations
Confidence
High

Evidence c78c4104b9
JSON

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

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

Appears in Networks:
Annotations
Confidence
High

Evidence 9ddb79fdc8
JSON

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].

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

Appears in Networks:
Annotations
Confidence
High

Evidence 003e65dd0e
JSON

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].

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Endoplasmic Reticulum

Evidence fac27d0fd6
JSON

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].

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

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence 16a2271768
JSON

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

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

Evidence 2bb41fd1fb
JSON

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].

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

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence 3def63fd3b
JSON

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

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

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence 57a9dbf510
JSON

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].

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

Evidence 20d04a0bed
JSON

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].

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

Evidence 76d7bf8995
JSON

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

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

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence 035eeeed02
JSON

Prabhudesai et al. showed that this molecule is able to inhibit the aggregation of a-syn in vitro and in a zebrafish model expressing human wild-type a-syn in neurons where CLR01 reduced apoptosis and improved embryo survival [127].

a(HBP:HBP00094) decreases a(HBP:HBP00016) View Subject | View Object

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

a(HBP:HBP00094) decreases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Brain
MeSH
Cerebrospinal Fluid
MeSH
Serum

Evidence 116f7bf950
JSON

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].

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

Appears in Networks:
Annotations
Confidence
High

Evidence f25247c2f1
JSON

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.

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

Evidence 88cb5ca5a0
JSON

First, a-syn oligomers bind synaptobrevin, a component of the SNARE complex required for synaptic vesicle fusion, and prevent the formation of the SNARE complex [23].

complex(a(HBP:HBP00093), p(HGNC:VAMP1)) decreases bp(GO:"SNARE complex assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Microglia

Evidence 455d9b5c3e
JSON

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].

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

Appears in Networks:
Annotations
Confidence
High
MeSH
Endoplasmic Reticulum

Evidence 4a4730c66a
JSON

Finally, Parkinson’s disease patients carrying familial mutations in the parkin gene, and some of those with the LRRK2 G2019S mutation, show neuronal degeneration in the absence of Lewy body formation [28, 50].

p(HGNC:LRRK2, var("p.Gly2019Ser")) increases path(MESH:"Neurodegenerative Diseases") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:PRKN, var("?")) increases path(MESH:"Neurodegenerative Diseases") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 6cffd65ff4
JSON

Over the past two decades, the pre-synaptic protein alphasynuclein (a-syn) has been irrefutably tied to the neurodegenerative disorder Parkinson’s disease.

p(HGNC:SNCA) association path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

path(MESH:"Parkinson Disease") association p(HGNC:SNCA) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 84a80c0f89
JSON

the point mutation in SNCA (A53T) was demonstrated to cause autosomal dominant Parkinson’s disease [126] and several other point mutations (A30P, E46K, H50Q, G51D and A53E) have since been shown to cause familial forms of Parkinson’s disease and dementia with Lewy bodies (DLB) [4, 79, 84, 119, 129, 167].

p(HGNC:SNCA, var("p.Ala30Pro")) increases path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:SNCA, var("p.Ala30Pro")) increases path(MESH:"Lewy Body Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:SNCA, var("p.Ala53Glu")) increases path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:SNCA, var("p.Ala53Thr")) increases path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:SNCA, var("p.Glu46Lys")) increases path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:SNCA, var("p.Gly51Asp")) increases path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:SNCA, var("p.His50Gln")) increases path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence dad3ce14f8
JSON

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].

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

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

Evidence b756cecd3f
JSON

USP19 promoted the secretion of a-syn, suggesting that MAPS is an unconventional secretion pathway utilized by a-syn, particularly under conditions of proteasomal impairment, which has been repeatedly linked to Parkinson’s disease.

p(HGNC:USP19) increases sec(p(HGNC:SNCA)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Microglia

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