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Genome-wide screen for modifiers of Parkinson's disease genes in Drosophila.

Fernandes C, Rao Y - Mol Brain (2011)

Bottom Line: Among them, opa1 and drp1 have been previously implicated in the PD pathways, whereas debra (dbr), Pi3K21B and β4GalNAcTA are novel PD-interacting genes.We took an unbiased genetic approach to systematically isolate modifiers of PD genes in Drosophila.Further study of novel PD-interacting genes will shed new light on the function of PD genes and help in the development of new therapeutic strategies for treating Parkinson's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, McGill University Health Centre, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada.

ABSTRACT

Background: Mutations in parkin and PTEN-induced kinase 1 (Pink1) lead to autosomal recessive forms of Parkinson's disease (PD). parkin and Pink1 encode a ubiquitin-protein ligase and a mitochondrially localized serine/threonine kinase, respectively. Recent studies have implicated Parkin and Pink1 in a common and evolutionarily conserved pathway for protecting mitochondrial integrity.

Results: To systematically identify novel components of the PD pathways, we generated a genetic background that allowed us to perform a genome-wide F1 screen for modifiers of Drosophila parkin (park) and Pink1 mutant phenotype. From screening ~80% of the fly genome, we identified a number of cytological regions that interact with park and/or Pink1. Among them, four cytological regions were selected for identifying corresponding PD-interacting genes. By analyzing smaller deficiency chromosomes, available transgenic RNAi lines, and P-element insertions, we identified five PD-interacting genes. Among them, opa1 and drp1 have been previously implicated in the PD pathways, whereas debra (dbr), Pi3K21B and β4GalNAcTA are novel PD-interacting genes.

Conclusions: We took an unbiased genetic approach to systematically isolate modifiers of PD genes in Drosophila. Further study of novel PD-interacting genes will shed new light on the function of PD genes and help in the development of new therapeutic strategies for treating Parkinson's disease.

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Molecular characterization of two PD suppressor-containing cytological regions 21B7-21C2 and 50E4-50F6. A, Characterization of the PD-interacting cytological region 21B7-21C2. B, Characterization of the PD-interacting cytological region 50E4-50F6. The regions uncovered by the deficiencies used in the experiments are indicated (dashed line). The effect of each deficiency is indicated as suppression (+) or no suppression (-). The genes (arrows) are listed according to their genomic location. opa1EY09863 is an opal loss-of-function allele in which a P-element-containing sequence is inserted into the opa1 locus. Df(2R)β4GalNAcTA[20.1] and β4GalNAcTA4.1 were generated by imprecise excision [47]. In the Df(2R)β4GalNAcTA[20.1] allele, both β4GalNAcTA and CG8531 are deleted, while 610 base-pair sequence in the β4GalNAcTA gene is deleted in the β4GalNAcTA4.1 allele.
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Figure 4: Molecular characterization of two PD suppressor-containing cytological regions 21B7-21C2 and 50E4-50F6. A, Characterization of the PD-interacting cytological region 21B7-21C2. B, Characterization of the PD-interacting cytological region 50E4-50F6. The regions uncovered by the deficiencies used in the experiments are indicated (dashed line). The effect of each deficiency is indicated as suppression (+) or no suppression (-). The genes (arrows) are listed according to their genomic location. opa1EY09863 is an opal loss-of-function allele in which a P-element-containing sequence is inserted into the opa1 locus. Df(2R)β4GalNAcTA[20.1] and β4GalNAcTA4.1 were generated by imprecise excision [47]. In the Df(2R)β4GalNAcTA[20.1] allele, both β4GalNAcTA and CG8531 are deleted, while 610 base-pair sequence in the β4GalNAcTA gene is deleted in the β4GalNAcTA4.1 allele.

Mentions: Reducing the dosage of the cytological region 21B7-21C2, uncovered by the deficiency chromosome Df(2L)BSC106, suppressed both park and Pink1 wing phenotype (Table 2 and 5). From a collection of smaller deficiencies mapped within this region, we identified two overlapping deficiencies Df(2L)BSC454 and Df(2L)Pi3K21B, which like Df(2L)BSC106, both suppressed park and Pink1 wing phenotype (Figure 4A). The cytological region deleted in both Df(2L)BSC454 and Df(2L)Pi3K21B, contains four genes Hop, Pi3K21B, Plc21C and U2af38.


Genome-wide screen for modifiers of Parkinson's disease genes in Drosophila.

Fernandes C, Rao Y - Mol Brain (2011)

Molecular characterization of two PD suppressor-containing cytological regions 21B7-21C2 and 50E4-50F6. A, Characterization of the PD-interacting cytological region 21B7-21C2. B, Characterization of the PD-interacting cytological region 50E4-50F6. The regions uncovered by the deficiencies used in the experiments are indicated (dashed line). The effect of each deficiency is indicated as suppression (+) or no suppression (-). The genes (arrows) are listed according to their genomic location. opa1EY09863 is an opal loss-of-function allele in which a P-element-containing sequence is inserted into the opa1 locus. Df(2R)β4GalNAcTA[20.1] and β4GalNAcTA4.1 were generated by imprecise excision [47]. In the Df(2R)β4GalNAcTA[20.1] allele, both β4GalNAcTA and CG8531 are deleted, while 610 base-pair sequence in the β4GalNAcTA gene is deleted in the β4GalNAcTA4.1 allele.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 4: Molecular characterization of two PD suppressor-containing cytological regions 21B7-21C2 and 50E4-50F6. A, Characterization of the PD-interacting cytological region 21B7-21C2. B, Characterization of the PD-interacting cytological region 50E4-50F6. The regions uncovered by the deficiencies used in the experiments are indicated (dashed line). The effect of each deficiency is indicated as suppression (+) or no suppression (-). The genes (arrows) are listed according to their genomic location. opa1EY09863 is an opal loss-of-function allele in which a P-element-containing sequence is inserted into the opa1 locus. Df(2R)β4GalNAcTA[20.1] and β4GalNAcTA4.1 were generated by imprecise excision [47]. In the Df(2R)β4GalNAcTA[20.1] allele, both β4GalNAcTA and CG8531 are deleted, while 610 base-pair sequence in the β4GalNAcTA gene is deleted in the β4GalNAcTA4.1 allele.
Mentions: Reducing the dosage of the cytological region 21B7-21C2, uncovered by the deficiency chromosome Df(2L)BSC106, suppressed both park and Pink1 wing phenotype (Table 2 and 5). From a collection of smaller deficiencies mapped within this region, we identified two overlapping deficiencies Df(2L)BSC454 and Df(2L)Pi3K21B, which like Df(2L)BSC106, both suppressed park and Pink1 wing phenotype (Figure 4A). The cytological region deleted in both Df(2L)BSC454 and Df(2L)Pi3K21B, contains four genes Hop, Pi3K21B, Plc21C and U2af38.

Bottom Line: Among them, opa1 and drp1 have been previously implicated in the PD pathways, whereas debra (dbr), Pi3K21B and β4GalNAcTA are novel PD-interacting genes.We took an unbiased genetic approach to systematically isolate modifiers of PD genes in Drosophila.Further study of novel PD-interacting genes will shed new light on the function of PD genes and help in the development of new therapeutic strategies for treating Parkinson's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, McGill University Health Centre, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada.

ABSTRACT

Background: Mutations in parkin and PTEN-induced kinase 1 (Pink1) lead to autosomal recessive forms of Parkinson's disease (PD). parkin and Pink1 encode a ubiquitin-protein ligase and a mitochondrially localized serine/threonine kinase, respectively. Recent studies have implicated Parkin and Pink1 in a common and evolutionarily conserved pathway for protecting mitochondrial integrity.

Results: To systematically identify novel components of the PD pathways, we generated a genetic background that allowed us to perform a genome-wide F1 screen for modifiers of Drosophila parkin (park) and Pink1 mutant phenotype. From screening ~80% of the fly genome, we identified a number of cytological regions that interact with park and/or Pink1. Among them, four cytological regions were selected for identifying corresponding PD-interacting genes. By analyzing smaller deficiency chromosomes, available transgenic RNAi lines, and P-element insertions, we identified five PD-interacting genes. Among them, opa1 and drp1 have been previously implicated in the PD pathways, whereas debra (dbr), Pi3K21B and β4GalNAcTA are novel PD-interacting genes.

Conclusions: We took an unbiased genetic approach to systematically isolate modifiers of PD genes in Drosophila. Further study of novel PD-interacting genes will shed new light on the function of PD genes and help in the development of new therapeutic strategies for treating Parkinson's disease.

Show MeSH
Related in: MedlinePlus