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A functional misexpression screen uncovers a role for enabled in progressive neurodegeneration.

Rezával C, Berni J, Gorostiza EA, Werbajh S, Fagilde MM, Fernández MP, Beckwith EJ, Aranovich EJ, Sabio y García CA, Ceriani MF - PLoS ONE (2008)

Bottom Line: One of the interesting candidates showing progressive arrhythmicity has reduced enabled (ena) levels. ena down-regulation gave rise to progressive vacuolization in specific regions of the adult brain.Abnormal staining of pre-synaptic markers such as cystein string protein (CSP) suggest that axonal transport could underlie the neurodegeneration observed in the mutant.Reduced ena levels correlated with increased apoptosis, which could be rescued in the presence of p35, a general Caspase inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Genética del Comportamiento, Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas-Buenos Aires (IIB-BA, CONICET), Buenos Aires, Argentina.

ABSTRACT
Drosophila is a well-established model to study the molecular basis of neurodegenerative diseases. We carried out a misexpression screen to identify genes involved in neurodegeneration examining locomotor behavior in young and aged flies. We hypothesized that a progressive loss of rhythmic activity could reveal novel genes involved in neurodegenerative mechanisms. One of the interesting candidates showing progressive arrhythmicity has reduced enabled (ena) levels. ena down-regulation gave rise to progressive vacuolization in specific regions of the adult brain. Abnormal staining of pre-synaptic markers such as cystein string protein (CSP) suggest that axonal transport could underlie the neurodegeneration observed in the mutant. Reduced ena levels correlated with increased apoptosis, which could be rescued in the presence of p35, a general Caspase inhibitor. Thus, this mutant recapitulates two important features of human neurodegenerative diseases, i.e., vulnerability of certain neuronal populations and progressive degeneration, offering a unique scenario in which to unravel the specific mechanisms in an easily tractable organism.

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Related in: MedlinePlus

A novel P[UAS] insertion line shows progressive behavioral defects.Crossing P[UAS]117 to the pdf-gal4 driver results in a significant decrease in the rhythmicity of old flies. (A) Representative double plotted actograms for young (3d) and aged (21d) flies of pdf-gal4/ P[UAS]117 along with the corresponding controls. (B) The percentage of rhythmic flies for each strain is shown. Older pdf-gal4/ P[UAS]117 flies are significantly different from their younger counterparts and from the aged controls (* p<0.05). Experiments were repeated at least three times. Additional details are included in Table S2. (C) No progressive decrease in daily activity was observed in either line. Although no differences were found between pdf-gal4/ P[UAS]117 and pdf-gal4/+ individuals, young and aged heterozygous P[UAS]117 flies were overall more active (* p<0.05; ** p<0.01).
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pone-0003332-g002: A novel P[UAS] insertion line shows progressive behavioral defects.Crossing P[UAS]117 to the pdf-gal4 driver results in a significant decrease in the rhythmicity of old flies. (A) Representative double plotted actograms for young (3d) and aged (21d) flies of pdf-gal4/ P[UAS]117 along with the corresponding controls. (B) The percentage of rhythmic flies for each strain is shown. Older pdf-gal4/ P[UAS]117 flies are significantly different from their younger counterparts and from the aged controls (* p<0.05). Experiments were repeated at least three times. Additional details are included in Table S2. (C) No progressive decrease in daily activity was observed in either line. Although no differences were found between pdf-gal4/ P[UAS]117 and pdf-gal4/+ individuals, young and aged heterozygous P[UAS]117 flies were overall more active (* p<0.05; ** p<0.01).

Mentions: In particular, pdf-gal4/P[UAS]117 (from now on referred to as pdf>P[UAS]117) exhibited an age-dependent decrease in the percentage of rhythmicity (Fig. 2 A–B and Table S2) resulting from an abnormal consolidation of the subjective day activity during constant conditions. This phenotype was not observed when analyzing in parallel a single copy of the pdf-gal4 driver or the P[UAS]117 insertion in a heterozygous state (Fig. 2A–B). Overall activity, on the other hand, did not show any significant age-associated decline in pdf-gal4/P[UAS]117 and controls (Fig. 2C); moreover, no significant differences in overall activity were observed between aged pdf-gal4/P[UAS]117 and the pdf-gal4 heterozygous control, suggesting that the progressive arrhythmicity characteristic of pdf-gal4/P[UAS]117 is not the result of a drastic reduction in total activity.


A functional misexpression screen uncovers a role for enabled in progressive neurodegeneration.

Rezával C, Berni J, Gorostiza EA, Werbajh S, Fagilde MM, Fernández MP, Beckwith EJ, Aranovich EJ, Sabio y García CA, Ceriani MF - PLoS ONE (2008)

A novel P[UAS] insertion line shows progressive behavioral defects.Crossing P[UAS]117 to the pdf-gal4 driver results in a significant decrease in the rhythmicity of old flies. (A) Representative double plotted actograms for young (3d) and aged (21d) flies of pdf-gal4/ P[UAS]117 along with the corresponding controls. (B) The percentage of rhythmic flies for each strain is shown. Older pdf-gal4/ P[UAS]117 flies are significantly different from their younger counterparts and from the aged controls (* p<0.05). Experiments were repeated at least three times. Additional details are included in Table S2. (C) No progressive decrease in daily activity was observed in either line. Although no differences were found between pdf-gal4/ P[UAS]117 and pdf-gal4/+ individuals, young and aged heterozygous P[UAS]117 flies were overall more active (* p<0.05; ** p<0.01).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553195&req=5

pone-0003332-g002: A novel P[UAS] insertion line shows progressive behavioral defects.Crossing P[UAS]117 to the pdf-gal4 driver results in a significant decrease in the rhythmicity of old flies. (A) Representative double plotted actograms for young (3d) and aged (21d) flies of pdf-gal4/ P[UAS]117 along with the corresponding controls. (B) The percentage of rhythmic flies for each strain is shown. Older pdf-gal4/ P[UAS]117 flies are significantly different from their younger counterparts and from the aged controls (* p<0.05). Experiments were repeated at least three times. Additional details are included in Table S2. (C) No progressive decrease in daily activity was observed in either line. Although no differences were found between pdf-gal4/ P[UAS]117 and pdf-gal4/+ individuals, young and aged heterozygous P[UAS]117 flies were overall more active (* p<0.05; ** p<0.01).
Mentions: In particular, pdf-gal4/P[UAS]117 (from now on referred to as pdf>P[UAS]117) exhibited an age-dependent decrease in the percentage of rhythmicity (Fig. 2 A–B and Table S2) resulting from an abnormal consolidation of the subjective day activity during constant conditions. This phenotype was not observed when analyzing in parallel a single copy of the pdf-gal4 driver or the P[UAS]117 insertion in a heterozygous state (Fig. 2A–B). Overall activity, on the other hand, did not show any significant age-associated decline in pdf-gal4/P[UAS]117 and controls (Fig. 2C); moreover, no significant differences in overall activity were observed between aged pdf-gal4/P[UAS]117 and the pdf-gal4 heterozygous control, suggesting that the progressive arrhythmicity characteristic of pdf-gal4/P[UAS]117 is not the result of a drastic reduction in total activity.

Bottom Line: One of the interesting candidates showing progressive arrhythmicity has reduced enabled (ena) levels. ena down-regulation gave rise to progressive vacuolization in specific regions of the adult brain.Abnormal staining of pre-synaptic markers such as cystein string protein (CSP) suggest that axonal transport could underlie the neurodegeneration observed in the mutant.Reduced ena levels correlated with increased apoptosis, which could be rescued in the presence of p35, a general Caspase inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Genética del Comportamiento, Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas-Buenos Aires (IIB-BA, CONICET), Buenos Aires, Argentina.

ABSTRACT
Drosophila is a well-established model to study the molecular basis of neurodegenerative diseases. We carried out a misexpression screen to identify genes involved in neurodegeneration examining locomotor behavior in young and aged flies. We hypothesized that a progressive loss of rhythmic activity could reveal novel genes involved in neurodegenerative mechanisms. One of the interesting candidates showing progressive arrhythmicity has reduced enabled (ena) levels. ena down-regulation gave rise to progressive vacuolization in specific regions of the adult brain. Abnormal staining of pre-synaptic markers such as cystein string protein (CSP) suggest that axonal transport could underlie the neurodegeneration observed in the mutant. Reduced ena levels correlated with increased apoptosis, which could be rescued in the presence of p35, a general Caspase inhibitor. Thus, this mutant recapitulates two important features of human neurodegenerative diseases, i.e., vulnerability of certain neuronal populations and progressive degeneration, offering a unique scenario in which to unravel the specific mechanisms in an easily tractable organism.

Show MeSH
Related in: MedlinePlus