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The TRiC/CCT chaperone is implicated in Alzheimer's disease based on patient GWAS and an RNAi screen in Aβ-expressing Caenorhabditis elegans.

Khabirova E, Moloney A, Marciniak SJ, Williams J, Lomas DA, Oliver SG, Favrin G, Sattelle DB, Crowther DC - PLoS ONE (2014)

Bottom Line: To increase the sensitivity of our analysis, we then considered the physical interactors (+1 interactome) of the products of the genes in both the worm and the white+grey zone lists.When we consider these worm and GWAS gene lists we find that 4 of the 60 worm genes have a +1 interactome overlap that is larger than expected by chance.Two of these genes form a chaperonin complex, the third is closely associated with this complex and the fourth gene codes for actin, the major substrate of the same chaperonin.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.

ABSTRACT
The human Aβ peptide causes progressive paralysis when expressed in the muscles of the nematode worm, C. elegans. We have exploited this model of Aβ toxicity by carrying out an RNAi screen to identify genes whose reduced expression modifies the severity of this locomotor phenotype. Our initial finding was that none of the human orthologues of these worm genes is identical with the genome-wide significant GWAS genes reported to date (the "white zone"); moreover there was no identity between worm screen hits and the longer list of GWAS genes which included those with borderline levels of significance (the "grey zone"). This indicates that Aβ toxicity should not be considered as equivalent to sporadic AD. To increase the sensitivity of our analysis, we then considered the physical interactors (+1 interactome) of the products of the genes in both the worm and the white+grey zone lists. When we consider these worm and GWAS gene lists we find that 4 of the 60 worm genes have a +1 interactome overlap that is larger than expected by chance. Two of these genes form a chaperonin complex, the third is closely associated with this complex and the fourth gene codes for actin, the major substrate of the same chaperonin.

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Distribution of rankings of worm models of neurodegenerative diseases.The x-axis represents the log of the gene ranking bin boundaries, arranged in decreasing gene-product connectedness from left to right. The y-axis represents the log of the fraction of genes in each bin (where 100% is 135, 23, 22 & 52 genes for panels A, B, C & D respectively). The dashed line shows the linear regression for the worm screen results. The results of the screens are shown as black diamonds and results of random simulations are shown as empty triangles. (A) polyglutamine screen; (B) α-synuclein screen; (C) tau screen; (D) GWAS candidate white+grey zone genes for AD.
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pone-0102985-g004: Distribution of rankings of worm models of neurodegenerative diseases.The x-axis represents the log of the gene ranking bin boundaries, arranged in decreasing gene-product connectedness from left to right. The y-axis represents the log of the fraction of genes in each bin (where 100% is 135, 23, 22 & 52 genes for panels A, B, C & D respectively). The dashed line shows the linear regression for the worm screen results. The results of the screens are shown as black diamonds and results of random simulations are shown as empty triangles. (A) polyglutamine screen; (B) α-synuclein screen; (C) tau screen; (D) GWAS candidate white+grey zone genes for AD.

Mentions: To understand whether such a bias is a common feature of worm RNAi screens, we repeated a similar analysis for three published modifier screens of human neurodegenerative disorders (modelling polyglutamine [22] [Table S2a], tau [23]Table S2b] and alpha-synuclein pathogenesis [24] [Table S2c]) and, congruent with our results, we also found a skew in these screens towards highly interconnected genes (Fig. 4 A–C). Using a one-tailed Student’s t-test we observed that for the polyQ (p = 0.0002, Fig. 4, panel A), the α-synuclein (p = 0.04, panel B), and the tau (p = 0.04, panel C) screens, the gradient of the linear regression lines was significantly less than for the Monte-Carlo-generated data. By contrast the equivalent gradient of the GWAS white+grey zone genes was robustly zero (p = 0.22, two-tailed, panel D).


The TRiC/CCT chaperone is implicated in Alzheimer's disease based on patient GWAS and an RNAi screen in Aβ-expressing Caenorhabditis elegans.

Khabirova E, Moloney A, Marciniak SJ, Williams J, Lomas DA, Oliver SG, Favrin G, Sattelle DB, Crowther DC - PLoS ONE (2014)

Distribution of rankings of worm models of neurodegenerative diseases.The x-axis represents the log of the gene ranking bin boundaries, arranged in decreasing gene-product connectedness from left to right. The y-axis represents the log of the fraction of genes in each bin (where 100% is 135, 23, 22 & 52 genes for panels A, B, C & D respectively). The dashed line shows the linear regression for the worm screen results. The results of the screens are shown as black diamonds and results of random simulations are shown as empty triangles. (A) polyglutamine screen; (B) α-synuclein screen; (C) tau screen; (D) GWAS candidate white+grey zone genes for AD.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4117641&req=5

pone-0102985-g004: Distribution of rankings of worm models of neurodegenerative diseases.The x-axis represents the log of the gene ranking bin boundaries, arranged in decreasing gene-product connectedness from left to right. The y-axis represents the log of the fraction of genes in each bin (where 100% is 135, 23, 22 & 52 genes for panels A, B, C & D respectively). The dashed line shows the linear regression for the worm screen results. The results of the screens are shown as black diamonds and results of random simulations are shown as empty triangles. (A) polyglutamine screen; (B) α-synuclein screen; (C) tau screen; (D) GWAS candidate white+grey zone genes for AD.
Mentions: To understand whether such a bias is a common feature of worm RNAi screens, we repeated a similar analysis for three published modifier screens of human neurodegenerative disorders (modelling polyglutamine [22] [Table S2a], tau [23]Table S2b] and alpha-synuclein pathogenesis [24] [Table S2c]) and, congruent with our results, we also found a skew in these screens towards highly interconnected genes (Fig. 4 A–C). Using a one-tailed Student’s t-test we observed that for the polyQ (p = 0.0002, Fig. 4, panel A), the α-synuclein (p = 0.04, panel B), and the tau (p = 0.04, panel C) screens, the gradient of the linear regression lines was significantly less than for the Monte-Carlo-generated data. By contrast the equivalent gradient of the GWAS white+grey zone genes was robustly zero (p = 0.22, two-tailed, panel D).

Bottom Line: To increase the sensitivity of our analysis, we then considered the physical interactors (+1 interactome) of the products of the genes in both the worm and the white+grey zone lists.When we consider these worm and GWAS gene lists we find that 4 of the 60 worm genes have a +1 interactome overlap that is larger than expected by chance.Two of these genes form a chaperonin complex, the third is closely associated with this complex and the fourth gene codes for actin, the major substrate of the same chaperonin.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.

ABSTRACT
The human Aβ peptide causes progressive paralysis when expressed in the muscles of the nematode worm, C. elegans. We have exploited this model of Aβ toxicity by carrying out an RNAi screen to identify genes whose reduced expression modifies the severity of this locomotor phenotype. Our initial finding was that none of the human orthologues of these worm genes is identical with the genome-wide significant GWAS genes reported to date (the "white zone"); moreover there was no identity between worm screen hits and the longer list of GWAS genes which included those with borderline levels of significance (the "grey zone"). This indicates that Aβ toxicity should not be considered as equivalent to sporadic AD. To increase the sensitivity of our analysis, we then considered the physical interactors (+1 interactome) of the products of the genes in both the worm and the white+grey zone lists. When we consider these worm and GWAS gene lists we find that 4 of the 60 worm genes have a +1 interactome overlap that is larger than expected by chance. Two of these genes form a chaperonin complex, the third is closely associated with this complex and the fourth gene codes for actin, the major substrate of the same chaperonin.

Show MeSH
Related in: MedlinePlus