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A genetic screen identifies Tor as an interactor of VAPB in a Drosophila model of amyotrophic lateral sclerosis.

Deivasigamani S, Verma HK, Ueda R, Ratnaparkhi A, Ratnaparkhi GS - Biol Open (2014)

Bottom Line: One key modifier identified was Tor, whose knockdown reversed the large bouton phenotype associated with VAP(P58S) expression in neurons.A similar reversal was seen by over-expressing Tuberous Sclerosis Complex (Tsc1,2) that negatively regulates TOR signaling as also by reduction of S6K activity.In comparison, the small bouton phenotype associated with VAP(wt) expression was reversed with Tsc1 knock down as well as S6K-CA expression.

View Article: PubMed Central - PubMed

Affiliation: Indian Institute of Science Education and Research, Pune 411021, India.

No MeSH data available.


Related in: MedlinePlus

An integrated network of dVAP genetic interactors.An extended network of dVAP network was built by integrating VAP interaction data from our screen (103 genes) with known physical interactors of dVAP. The extended network (not shown) includes 406 genes and 953 edges. (A) Analysis indicated that 36 modifiers (displayed as circles), which are a subset of the 103 modifiers discovered, interact physically among themselves. Blue connecting lines (edges) indicate physical interaction. (B) Drosophila homologs of known ALS causing loci, TBPH, Alsin and sod1 are suppressors of dVAP function and are part of the genetic network. The genotype for each cross is Sca-Gal4/+; UAS-VAP/UAS-Gene-RNAi. For each figure, average macro chaetae values from ten females are represented on the top right hand corner. (C) Thirty-five known physical interactors of VAP are a subset of the 2635 genes screened in this study. Of these, eight genes were found to be genetic interactors of VAP. SNAMA, tmod, lethal (1) G0222, epsilon-COP and Pex-19 are suppressors while Droj2, karyopherin beta3, Porin are enhancers.
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f02: An integrated network of dVAP genetic interactors.An extended network of dVAP network was built by integrating VAP interaction data from our screen (103 genes) with known physical interactors of dVAP. The extended network (not shown) includes 406 genes and 953 edges. (A) Analysis indicated that 36 modifiers (displayed as circles), which are a subset of the 103 modifiers discovered, interact physically among themselves. Blue connecting lines (edges) indicate physical interaction. (B) Drosophila homologs of known ALS causing loci, TBPH, Alsin and sod1 are suppressors of dVAP function and are part of the genetic network. The genotype for each cross is Sca-Gal4/+; UAS-VAP/UAS-Gene-RNAi. For each figure, average macro chaetae values from ten females are represented on the top right hand corner. (C) Thirty-five known physical interactors of VAP are a subset of the 2635 genes screened in this study. Of these, eight genes were found to be genetic interactors of VAP. SNAMA, tmod, lethal (1) G0222, epsilon-COP and Pex-19 are suppressors while Droj2, karyopherin beta3, Porin are enhancers.

Mentions: In order to identify components of the extended VAP network we built an interaction network between the modifiers identified in our screen and physical interactors of VAP using interactions from the databases STRING and GeneMANIA (Franceschini et al., 2013; Mostafavi et al., 2008) for Drosophila proteins. We considered only direct interactions and those separated by single node for building the integrated network. Our extended network contains 406 proteins, connected by 953 edges. Of the 103 modifiers identified in our screen, we found that 36 (35%) physically interact among themselves, connected by 53 edges (Fig. 2A). Of these, 13 physical interactions involving 12 proteins are ranked as medium confidence interactions (Combined score or weight of ≧0.4) by STRING or GeneMANIA. We also found that 61 (59%) of the genetic interactors can be linked via a common physical interactor. Based on predictions by DIOPT-DIST and literature mining, 23 of the 103 genes (22%) identified have been implicated to be involved in or regulating a human nervous system disease (supplementary material Table S2). This is significant considering that there is increasing evidence pointing to the idea of common network of genes/processes that are affected in several neurodegenerative diseases (Chen and Burgoyne, 2012; Shulman and De Jager, 2009). Our analysis leads us to believe that we have identified a core network of genes and proteins that interact with VAP and thus have the ability to modulate and be modulated by VAP function.


A genetic screen identifies Tor as an interactor of VAPB in a Drosophila model of amyotrophic lateral sclerosis.

Deivasigamani S, Verma HK, Ueda R, Ratnaparkhi A, Ratnaparkhi GS - Biol Open (2014)

An integrated network of dVAP genetic interactors.An extended network of dVAP network was built by integrating VAP interaction data from our screen (103 genes) with known physical interactors of dVAP. The extended network (not shown) includes 406 genes and 953 edges. (A) Analysis indicated that 36 modifiers (displayed as circles), which are a subset of the 103 modifiers discovered, interact physically among themselves. Blue connecting lines (edges) indicate physical interaction. (B) Drosophila homologs of known ALS causing loci, TBPH, Alsin and sod1 are suppressors of dVAP function and are part of the genetic network. The genotype for each cross is Sca-Gal4/+; UAS-VAP/UAS-Gene-RNAi. For each figure, average macro chaetae values from ten females are represented on the top right hand corner. (C) Thirty-five known physical interactors of VAP are a subset of the 2635 genes screened in this study. Of these, eight genes were found to be genetic interactors of VAP. SNAMA, tmod, lethal (1) G0222, epsilon-COP and Pex-19 are suppressors while Droj2, karyopherin beta3, Porin are enhancers.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4232771&req=5

f02: An integrated network of dVAP genetic interactors.An extended network of dVAP network was built by integrating VAP interaction data from our screen (103 genes) with known physical interactors of dVAP. The extended network (not shown) includes 406 genes and 953 edges. (A) Analysis indicated that 36 modifiers (displayed as circles), which are a subset of the 103 modifiers discovered, interact physically among themselves. Blue connecting lines (edges) indicate physical interaction. (B) Drosophila homologs of known ALS causing loci, TBPH, Alsin and sod1 are suppressors of dVAP function and are part of the genetic network. The genotype for each cross is Sca-Gal4/+; UAS-VAP/UAS-Gene-RNAi. For each figure, average macro chaetae values from ten females are represented on the top right hand corner. (C) Thirty-five known physical interactors of VAP are a subset of the 2635 genes screened in this study. Of these, eight genes were found to be genetic interactors of VAP. SNAMA, tmod, lethal (1) G0222, epsilon-COP and Pex-19 are suppressors while Droj2, karyopherin beta3, Porin are enhancers.
Mentions: In order to identify components of the extended VAP network we built an interaction network between the modifiers identified in our screen and physical interactors of VAP using interactions from the databases STRING and GeneMANIA (Franceschini et al., 2013; Mostafavi et al., 2008) for Drosophila proteins. We considered only direct interactions and those separated by single node for building the integrated network. Our extended network contains 406 proteins, connected by 953 edges. Of the 103 modifiers identified in our screen, we found that 36 (35%) physically interact among themselves, connected by 53 edges (Fig. 2A). Of these, 13 physical interactions involving 12 proteins are ranked as medium confidence interactions (Combined score or weight of ≧0.4) by STRING or GeneMANIA. We also found that 61 (59%) of the genetic interactors can be linked via a common physical interactor. Based on predictions by DIOPT-DIST and literature mining, 23 of the 103 genes (22%) identified have been implicated to be involved in or regulating a human nervous system disease (supplementary material Table S2). This is significant considering that there is increasing evidence pointing to the idea of common network of genes/processes that are affected in several neurodegenerative diseases (Chen and Burgoyne, 2012; Shulman and De Jager, 2009). Our analysis leads us to believe that we have identified a core network of genes and proteins that interact with VAP and thus have the ability to modulate and be modulated by VAP function.

Bottom Line: One key modifier identified was Tor, whose knockdown reversed the large bouton phenotype associated with VAP(P58S) expression in neurons.A similar reversal was seen by over-expressing Tuberous Sclerosis Complex (Tsc1,2) that negatively regulates TOR signaling as also by reduction of S6K activity.In comparison, the small bouton phenotype associated with VAP(wt) expression was reversed with Tsc1 knock down as well as S6K-CA expression.

View Article: PubMed Central - PubMed

Affiliation: Indian Institute of Science Education and Research, Pune 411021, India.

No MeSH data available.


Related in: MedlinePlus