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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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bnch is required for oogenesis and carbohydrate mobilization from yolk spheres. (A and B) Germline clones of bnchE14.1 give rise to malformed oocytes (B) compared with wt (A). The eggs are of significantly reduced size (∼1/3 to 2/3 of wild-type length). Few are laid and none are fertilized. The dorsal appendages are abnormally formed and their distance is somewhat widened. (C and D) Lysotracker staining reveals dramatic expansion of the acidic ooplasmic compartment in bnch11F5 (D) compared with wild-type oocytes (C). (E, E′, F, and F′) In bnchΔ2b mutant ooplasm PAS staining reveals dramatic expansion of red PAS positive β-spheres (F′, arrowheads) compared with the control (E′, arrowheads), whereas blue PAS-negative α-spheres are similar in size in bnch (F′, arrows) and control (E′, arrows) ooplasm.
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fig2: bnch is required for oogenesis and carbohydrate mobilization from yolk spheres. (A and B) Germline clones of bnchE14.1 give rise to malformed oocytes (B) compared with wt (A). The eggs are of significantly reduced size (∼1/3 to 2/3 of wild-type length). Few are laid and none are fertilized. The dorsal appendages are abnormally formed and their distance is somewhat widened. (C and D) Lysotracker staining reveals dramatic expansion of the acidic ooplasmic compartment in bnch11F5 (D) compared with wild-type oocytes (C). (E, E′, F, and F′) In bnchΔ2b mutant ooplasm PAS staining reveals dramatic expansion of red PAS positive β-spheres (F′, arrowheads) compared with the control (E′, arrowheads), whereas blue PAS-negative α-spheres are similar in size in bnch (F′, arrows) and control (E′, arrows) ooplasm.

Mentions: In the absence of bnch in the germline, few eggs are laid and none become fertilized. The eggs are small, varying from 1/3 to 2/3 of wild-type size (Fig. 2, A and D). The dorsal appendages are malformed and often positioned laterally compared with the wild type. These results indicate that bnch is required for oogenesis.


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)

bnch is required for oogenesis and carbohydrate mobilization from yolk spheres. (A and B) Germline clones of bnchE14.1 give rise to malformed oocytes (B) compared with wt (A). The eggs are of significantly reduced size (∼1/3 to 2/3 of wild-type length). Few are laid and none are fertilized. The dorsal appendages are abnormally formed and their distance is somewhat widened. (C and D) Lysotracker staining reveals dramatic expansion of the acidic ooplasmic compartment in bnch11F5 (D) compared with wild-type oocytes (C). (E, E′, F, and F′) In bnchΔ2b mutant ooplasm PAS staining reveals dramatic expansion of red PAS positive β-spheres (F′, arrowheads) compared with the control (E′, arrowheads), whereas blue PAS-negative α-spheres are similar in size in bnch (F′, arrows) and control (E′, arrows) ooplasm.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: bnch is required for oogenesis and carbohydrate mobilization from yolk spheres. (A and B) Germline clones of bnchE14.1 give rise to malformed oocytes (B) compared with wt (A). The eggs are of significantly reduced size (∼1/3 to 2/3 of wild-type length). Few are laid and none are fertilized. The dorsal appendages are abnormally formed and their distance is somewhat widened. (C and D) Lysotracker staining reveals dramatic expansion of the acidic ooplasmic compartment in bnch11F5 (D) compared with wild-type oocytes (C). (E, E′, F, and F′) In bnchΔ2b mutant ooplasm PAS staining reveals dramatic expansion of red PAS positive β-spheres (F′, arrowheads) compared with the control (E′, arrowheads), whereas blue PAS-negative α-spheres are similar in size in bnch (F′, arrows) and control (E′, arrows) ooplasm.
Mentions: In the absence of bnch in the germline, few eggs are laid and none become fertilized. The eggs are small, varying from 1/3 to 2/3 of wild-type size (Fig. 2, A and D). The dorsal appendages are malformed and often positioned laterally compared with the wild type. These results indicate that bnch is required for oogenesis.

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