Limits...
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.

Show MeSH

Related in: MedlinePlus

Molecular characterization of the PD-interacting cytological region 21A1-21B7. Genes (arrows) are listed according to their genomic location. The regions uncovered by the deficiencies used in the experiments are indicated (dashed lines). The effect of each deficiency is indicated as enhancement (+) or no enhancement (-).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3094290&req=5

Figure 3: Molecular characterization of the PD-interacting cytological region 21A1-21B7. Genes (arrows) are listed according to their genomic location. The regions uncovered by the deficiencies used in the experiments are indicated (dashed lines). The effect of each deficiency is indicated as enhancement (+) or no enhancement (-).

Mentions: From above screens, we found that reducing the dosage of the cytological region 21A1-21B7-8, deleted in the deficiency chromosome Df(2L) net-PMF, enhanced both park and Pink1 wing phenotype (Table 1 and 4). To identify the corresponding PD-interacting gene within this cytological region, we tested additional deficiency lines that carry smaller deletions within this region. We found that similar enhancement was observed when a smaller deficiency chromosome Df(2L)ED5878 was crossed into park or Pink1 knockdown background (Figure 3). Twenty two genes are disrupted in this deficiency chromosome, including dbr, galectin, CG11374, net, CG11376, Sam-S, CG4822, Gs1, CG31976, CG3709, CG11377, CG13694, CG31975, CG11455, Nhe1, CG3164, CG31974, CG3436, CG11454, CG33635, CG42399 and spen. Interestingly, we found that another smaller deficiency Df(2L) ED2809 in which only the debra (dbr) gene is deleted, also enhanced the park knockdown phenotype (~50% increase in penetrance compared to park RNAi alone, n = 104). Taken together, these results suggest strongly that dbr is largely, if not entirely, responsible for the observed interaction with PD genes.


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

Fernandes C, Rao Y - Mol Brain (2011)

Molecular characterization of the PD-interacting cytological region 21A1-21B7. Genes (arrows) are listed according to their genomic location. The regions uncovered by the deficiencies used in the experiments are indicated (dashed lines). The effect of each deficiency is indicated as enhancement (+) or no enhancement (-).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3094290&req=5

Figure 3: Molecular characterization of the PD-interacting cytological region 21A1-21B7. Genes (arrows) are listed according to their genomic location. The regions uncovered by the deficiencies used in the experiments are indicated (dashed lines). The effect of each deficiency is indicated as enhancement (+) or no enhancement (-).
Mentions: From above screens, we found that reducing the dosage of the cytological region 21A1-21B7-8, deleted in the deficiency chromosome Df(2L) net-PMF, enhanced both park and Pink1 wing phenotype (Table 1 and 4). To identify the corresponding PD-interacting gene within this cytological region, we tested additional deficiency lines that carry smaller deletions within this region. We found that similar enhancement was observed when a smaller deficiency chromosome Df(2L)ED5878 was crossed into park or Pink1 knockdown background (Figure 3). Twenty two genes are disrupted in this deficiency chromosome, including dbr, galectin, CG11374, net, CG11376, Sam-S, CG4822, Gs1, CG31976, CG3709, CG11377, CG13694, CG31975, CG11455, Nhe1, CG3164, CG31974, CG3436, CG11454, CG33635, CG42399 and spen. Interestingly, we found that another smaller deficiency Df(2L) ED2809 in which only the debra (dbr) gene is deleted, also enhanced the park knockdown phenotype (~50% increase in penetrance compared to park RNAi alone, n = 104). Taken together, these results suggest strongly that dbr is largely, if not entirely, responsible for the observed interaction with PD genes.

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