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Entity

Name
Protein Aggregation, Pathological
Namespace
MeSH
Namespace Version
20181007
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/01c9daa61012b37dd0a1bc962521ba51a15b38f1/external/mesh-names.belns

Appears in Networks 6

In-Edges 26

a(CHEBI:sirolimus) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Treatment of cell, Drosophila, and mouse models of HD, SCA3/MJD, AD, PD, and ALS with the mTOR inhibitor rapamycin (or a derivative) reduces aggregation and suppresses disease (140– 143). PubMed:25784053

Annotations
Cell Ontology (CL)
motor neuron

a(MESH:"Molecular Chaperones") decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

As discussed above, one approach is to employ specialized molecular chaperone machines to release misfolded proteins from aggregates and direct them to the proteasome for degradation (19). PubMed:25784053

a(MESH:Lysosomes) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Alternatively, bulkier substrates, such as large inclusions, can be directed to the lysosome, a membrane-bound organelle containing a host of nonspecific proteases that can degrade a wide range of substrates (21). PubMed:25784053

bp(HBP:Proteostasis) association path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Proteome fidelity is maintained by the protein homeostasis (proteostasis) network (PN), a multi-compartmental system that coordinatesprotein synthesis, folding, disaggregation, and degradation (1). PubMed:25784053

complex(p(FPLX:HSPA), p(HGNC:DNAJB1), p(HGNC:HSPH1)) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Perhaps the most significant example of this process is that the HSP110 molecular chaperone, long considered simply a NEF, can catalyze protein disaggregation as part of a complex containing HSP70 and DNAJ/HSP40 (18). PubMed:25784053

p(HGNC:DNAJB1) negativeCorrelation path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Studies of chaperone levels in tissue culture and mouse models of polyQ disease showed that the levels of HSP70 (HSPA1A/B) and DNAJ/HSP40 (DNAJB1), as well as some cochaperones, decline with protein aggregation (64, 65). PubMed:25784053

p(FPLX:Proteasome) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

As discussed above, one approach is to employ specialized molecular chaperone machines to release misfolded proteins from aggregates and direct them to the proteasome for degradation (19). PubMed:25784053

p(HGNC:HSPA1A) negativeCorrelation path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Studies of chaperone levels in tissue culture and mouse models of polyQ disease showed that the levels of HSP70 (HSPA1A/B) and DNAJ/HSP40 (DNAJB1), as well as some cochaperones, decline with protein aggregation (64, 65). PubMed:25784053

p(HGNC:HSPA1B) negativeCorrelation path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Studies of chaperone levels in tissue culture and mouse models of polyQ disease showed that the levels of HSP70 (HSPA1A/B) and DNAJ/HSP40 (DNAJB1), as well as some cochaperones, decline with protein aggregation (64, 65). PubMed:25784053

path(MESH:"Neurodegenerative Diseases") association path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Protein aggregation is recognized as a hallmark of neurodegenerative disease by the consistent appearance of detergent-insoluble inclusions and aggregates in the nucleus and cytoplasm of neurons. PubMed:25784053

a(HBP:"3R tau") positiveCorrelation path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Right angle laser light scattering showed significantly greater scattered light intensity in all 4R tau isoforms when compared to 3R isoforms (one-way ANOVA with Holm-Sidak post-hoc, F(5, 18) = 60.22, p < 0.0001; Fig. 2A) PubMed:27574109

a(HBP:"3R tau") positiveCorrelation path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Similar results were seen in the ThS assay, where the 4R isoforms were significantly higher than 3R isoforms (one-way ANOVA with Holm-Sidak post-hoc, F(5, 18) = 19.99, p < 0.0001; Fig. 2B), and no differences were found in comparisons between the individual 4R isoforms or between the 3R isoforms PubMed:27574109

a(HBP:"4R tau") positiveCorrelation path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Right angle laser light scattering showed significantly greater scattered light intensity in all 4R tau isoforms when compared to 3R isoforms (one-way ANOVA with Holm-Sidak post-hoc, F(5, 18) = 60.22, p < 0.0001; Fig. 2A) PubMed:27574109

a(HBP:"4R tau") positiveCorrelation path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Similar results were seen in the ThS assay, where the 4R isoforms were significantly higher than 3R isoforms (one-way ANOVA with Holm-Sidak post-hoc, F(5, 18) = 19.99, p < 0.0001; Fig. 2B), and no differences were found in comparisons between the individual 4R isoforms or between the 3R isoforms PubMed:27574109

bp(MESH:Aging) increases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Not only does aging lead to an increased likelihood of protein misfolding and aggregation, it is compounded by a decrease in the efficiency of the protein degradation machinery. PubMed:29311797

act(p(FPLX:HSP90)) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Hsp90 requires ATP to perform these functions including protein degradation, protein folding, prevention of protein aggregation, and protein modification (Echeverría et al., 2011). PubMed:29311797

p(FPLX:HSP90) regulates path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

However, Hsp90 regulates tau and other aggregating proteins in coordination with a diverse group of co-chaperones (Schopf et al., 2017). PubMed:29311797

p(HGNC:PTGES3) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

As a co-chaperone, p23 works to suppress protein aggregation and exhibits chaperoning activity, although p23 is not able to refold proteins on its own (Freeman et al., 1996). PubMed:29311797

p(FPLX:HSPA) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

These studies revealed that an increase in levels of HSP70 reduced aggregation of disease-associated proteins, thus playing a neuroprotective role. PubMed:27491084

p(UNIPROT:P32589) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

The co- chaperone HSP40 (dHdj-1 and SIS1) and the nucleotide exchange factor SSE1 that specifically modulate HSP70 activity were also shown to suppress toxicity and aggregation in yeast and fly disease models (Chan et al., 2000; Krobitsch and Lindquist, 2000; Sadlish et al., 2008). PubMed:27491084

bp(GO:"chaperone-mediated autophagy") decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Moreover, HSP22 stimu- lates autophagy-mediated degradation of protein aggregates in an eIF2α-dependent manner [30]. PubMed:24563850

bp(HBP:misfolding) increases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

In those organismal states (e.g. ageing or diseases) where the chaperone network becomes deregulated, the accumulating non-native, misfolded or unfolded proteins can form (among others) fibrils, amyloids or large amorphous aggregates [15]. PubMed:24563850

p(FPLX:HSP90) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

n general, HSP90s are more specialized than other chaperones and are essential for survival in eukaryotic cells as they also are capable of binding non-native polypeptides (at the late stages of their folding) and preventing their aggregation [14]. PubMed:24563850

p(FPLX:HSPA) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

HSP70 chaperones have a diverse array of cellular functions but their major role is to ensure correct folding of newly synthesized proteins and to perform the refolding of proteins that are misfolded and/or aggregated. PubMed:24563850

p(HGNCGENEFAMILY:"Small heat shock proteins") decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

These chaperones provide high-affinity binding platforms for unfolded proteins and prevent protein aggregation specifically during stress conditions. PubMed:24563850

Out-Edges 12

path(MESH:"Protein Aggregation, Pathological") association bp(HBP:Proteostasis) View Subject | View Object

Proteome fidelity is maintained by the protein homeostasis (proteostasis) network (PN), a multi-compartmental system that coordinatesprotein synthesis, folding, disaggregation, and degradation (1). PubMed:25784053

path(MESH:"Protein Aggregation, Pathological") association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

Protein aggregation is recognized as a hallmark of neurodegenerative disease by the consistent appearance of detergent-insoluble inclusions and aggregates in the nucleus and cytoplasm of neurons. PubMed:25784053

path(MESH:"Protein Aggregation, Pathological") negativeCorrelation p(HGNC:HSPA1A) View Subject | View Object

Studies of chaperone levels in tissue culture and mouse models of polyQ disease showed that the levels of HSP70 (HSPA1A/B) and DNAJ/HSP40 (DNAJB1), as well as some cochaperones, decline with protein aggregation (64, 65). PubMed:25784053

path(MESH:"Protein Aggregation, Pathological") negativeCorrelation p(HGNC:HSPA1B) View Subject | View Object

Studies of chaperone levels in tissue culture and mouse models of polyQ disease showed that the levels of HSP70 (HSPA1A/B) and DNAJ/HSP40 (DNAJB1), as well as some cochaperones, decline with protein aggregation (64, 65). PubMed:25784053

path(MESH:"Protein Aggregation, Pathological") negativeCorrelation p(HGNC:DNAJB1) View Subject | View Object

Studies of chaperone levels in tissue culture and mouse models of polyQ disease showed that the levels of HSP70 (HSPA1A/B) and DNAJ/HSP40 (DNAJB1), as well as some cochaperones, decline with protein aggregation (64, 65). PubMed:25784053

path(MESH:"Protein Aggregation, Pathological") positiveCorrelation a(HBP:"3R tau") View Subject | View Object

Right angle laser light scattering showed significantly greater scattered light intensity in all 4R tau isoforms when compared to 3R isoforms (one-way ANOVA with Holm-Sidak post-hoc, F(5, 18) = 60.22, p < 0.0001; Fig. 2A) PubMed:27574109

path(MESH:"Protein Aggregation, Pathological") positiveCorrelation a(HBP:"3R tau") View Subject | View Object

Similar results were seen in the ThS assay, where the 4R isoforms were significantly higher than 3R isoforms (one-way ANOVA with Holm-Sidak post-hoc, F(5, 18) = 19.99, p < 0.0001; Fig. 2B), and no differences were found in comparisons between the individual 4R isoforms or between the 3R isoforms PubMed:27574109

path(MESH:"Protein Aggregation, Pathological") positiveCorrelation a(HBP:"4R tau") View Subject | View Object

Right angle laser light scattering showed significantly greater scattered light intensity in all 4R tau isoforms when compared to 3R isoforms (one-way ANOVA with Holm-Sidak post-hoc, F(5, 18) = 60.22, p < 0.0001; Fig. 2A) PubMed:27574109

path(MESH:"Protein Aggregation, Pathological") positiveCorrelation a(HBP:"4R tau") View Subject | View Object

Similar results were seen in the ThS assay, where the 4R isoforms were significantly higher than 3R isoforms (one-way ANOVA with Holm-Sidak post-hoc, F(5, 18) = 19.99, p < 0.0001; Fig. 2B), and no differences were found in comparisons between the individual 4R isoforms or between the 3R isoforms PubMed:27574109

path(MESH:"Protein Aggregation, Pathological") decreases act(p(HGNC:HSPA8)) View Subject | View Object

Here, we show that diverse disease-associated aggregates se- quester the highly abundant major chaperone heat shock cognate protein 70 (HSC70) to the point of functional collapse of an essential cellular process, clathrin-mediated endocytosis (CME). PubMed:24706768

path(MESH:"Protein Aggregation, Pathological") decreases bp(GO:"clathrin-dependent endocytosis") View Subject | View Object

Here, we show that diverse disease-associated aggregates se- quester the highly abundant major chaperone heat shock cognate protein 70 (HSC70) to the point of functional collapse of an essential cellular process, clathrin-mediated endocytosis (CME). PubMed:24706768

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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.