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Aberrant lysosomal carbohydrate storage accompanies endocytic defects and neurodegeneration in Drosophila benchwarmer.

Dermaut B, Norga KK, Kania A, Verstreken P, Pan H, Zhou Y, Callaerts P, Bellen HJ - J. Cell Biol. (2005)

Bottom Line: Here, we report that loss of Drosophila benchwarmer (bnch), a predicted lysosomal sugar carrier, leads to carbohydrate storage in yolk spheres during oogenesis and results in widespread accumulation of enlarged lysosomal and late endosomal inclusions.Finally, we find that loss of bnch strongly enhances tau neurotoxicity in a dose-dependent manner.We hypothesize that, in bnch, defective lysosomal carbohydrate efflux leads to endocytic defects with functional consequences in synaptic strength, neuronal viability, and tau neurotoxicity.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

ABSTRACT
Lysosomal storage is the most common cause of neurodegenerative brain disease in preadulthood. However, the underlying cellular mechanisms that lead to neuronal dysfunction are unknown. Here, we report that loss of Drosophila benchwarmer (bnch), a predicted lysosomal sugar carrier, leads to carbohydrate storage in yolk spheres during oogenesis and results in widespread accumulation of enlarged lysosomal and late endosomal inclusions. At the bnch larval neuromuscular junction, we observe similar inclusions and find defects in synaptic vesicle recycling at the level of endocytosis. In addition, loss of bnch slows endosome-to-lysosome trafficking in larval garland cells. In adult bnch flies, we observe age-dependent synaptic dysfunction and neuronal degeneration. Finally, we find that loss of bnch strongly enhances tau neurotoxicity in a dose-dependent manner. We hypothesize that, in bnch, defective lysosomal carbohydrate efflux leads to endocytic defects with functional consequences in synaptic strength, neuronal viability, and tau neurotoxicity.

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Impaired visual synaptic function in bnch escapers and aged eye mosaics. (A) ERG recordings in 1-d-old flies having mosaic bnch eyes are similar to wild type. In 40-d-old bnch eye mosaic flies, ERG recordings reveal reduced depolarization in response to light and smaller to absent on/off transients (arrowheads) with stronger phenotypes for bnch alleles with premature stop codons (11F5 and E14.1) compared with bnch missense allele (N). (B) ERGs of bnch adult escapers show a depolarization in response to light similar to controls but lack on/off transients (arrowheads) and exhibit slowed repolarization.
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fig7: Impaired visual synaptic function in bnch escapers and aged eye mosaics. (A) ERG recordings in 1-d-old flies having mosaic bnch eyes are similar to wild type. In 40-d-old bnch eye mosaic flies, ERG recordings reveal reduced depolarization in response to light and smaller to absent on/off transients (arrowheads) with stronger phenotypes for bnch alleles with premature stop codons (11F5 and E14.1) compared with bnch missense allele (N). (B) ERGs of bnch adult escapers show a depolarization in response to light similar to controls but lack on/off transients (arrowheads) and exhibit slowed repolarization.

Mentions: To examine the functional consequences of loss of bnch at visual synapses, we performed electroretinogram (ERG) recordings (Fig. 7). We found that 1-d-old mosaic animals show a normal depolarization in response to light and have normal on/off transients (Fig. 7 A). In agreement, they behave normally during phototaxis assays (unpublished data). However, in 40-d-old bnch mosaic flies but not control flies, ERG recordings consistently displayed reduced depolarization amplitudes and smaller or absent on/off transients (Fig. 7 A). These results show that, although normal at eclosion, phototransduction and visual synaptic transmission progressively deteriorate over a 40-d period in bnch mutant eyes.


Aberrant lysosomal carbohydrate storage accompanies endocytic defects and neurodegeneration in Drosophila benchwarmer.

Dermaut B, Norga KK, Kania A, Verstreken P, Pan H, Zhou Y, Callaerts P, Bellen HJ - J. Cell Biol. (2005)

Impaired visual synaptic function in bnch escapers and aged eye mosaics. (A) ERG recordings in 1-d-old flies having mosaic bnch eyes are similar to wild type. In 40-d-old bnch eye mosaic flies, ERG recordings reveal reduced depolarization in response to light and smaller to absent on/off transients (arrowheads) with stronger phenotypes for bnch alleles with premature stop codons (11F5 and E14.1) compared with bnch missense allele (N). (B) ERGs of bnch adult escapers show a depolarization in response to light similar to controls but lack on/off transients (arrowheads) and exhibit slowed repolarization.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171373&req=5

fig7: Impaired visual synaptic function in bnch escapers and aged eye mosaics. (A) ERG recordings in 1-d-old flies having mosaic bnch eyes are similar to wild type. In 40-d-old bnch eye mosaic flies, ERG recordings reveal reduced depolarization in response to light and smaller to absent on/off transients (arrowheads) with stronger phenotypes for bnch alleles with premature stop codons (11F5 and E14.1) compared with bnch missense allele (N). (B) ERGs of bnch adult escapers show a depolarization in response to light similar to controls but lack on/off transients (arrowheads) and exhibit slowed repolarization.
Mentions: To examine the functional consequences of loss of bnch at visual synapses, we performed electroretinogram (ERG) recordings (Fig. 7). We found that 1-d-old mosaic animals show a normal depolarization in response to light and have normal on/off transients (Fig. 7 A). In agreement, they behave normally during phototaxis assays (unpublished data). However, in 40-d-old bnch mosaic flies but not control flies, ERG recordings consistently displayed reduced depolarization amplitudes and smaller or absent on/off transients (Fig. 7 A). These results show that, although normal at eclosion, phototransduction and visual synaptic transmission progressively deteriorate over a 40-d period in bnch mutant eyes.

Bottom Line: Here, we report that loss of Drosophila benchwarmer (bnch), a predicted lysosomal sugar carrier, leads to carbohydrate storage in yolk spheres during oogenesis and results in widespread accumulation of enlarged lysosomal and late endosomal inclusions.Finally, we find that loss of bnch strongly enhances tau neurotoxicity in a dose-dependent manner.We hypothesize that, in bnch, defective lysosomal carbohydrate efflux leads to endocytic defects with functional consequences in synaptic strength, neuronal viability, and tau neurotoxicity.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

ABSTRACT
Lysosomal storage is the most common cause of neurodegenerative brain disease in preadulthood. However, the underlying cellular mechanisms that lead to neuronal dysfunction are unknown. Here, we report that loss of Drosophila benchwarmer (bnch), a predicted lysosomal sugar carrier, leads to carbohydrate storage in yolk spheres during oogenesis and results in widespread accumulation of enlarged lysosomal and late endosomal inclusions. At the bnch larval neuromuscular junction, we observe similar inclusions and find defects in synaptic vesicle recycling at the level of endocytosis. In addition, loss of bnch slows endosome-to-lysosome trafficking in larval garland cells. In adult bnch flies, we observe age-dependent synaptic dysfunction and neuronal degeneration. Finally, we find that loss of bnch strongly enhances tau neurotoxicity in a dose-dependent manner. We hypothesize that, in bnch, defective lysosomal carbohydrate efflux leads to endocytic defects with functional consequences in synaptic strength, neuronal viability, and tau neurotoxicity.

Show MeSH
Related in: MedlinePlus