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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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Cytoplasmic membranous inclusions accumulate in the bnch mutant visual system. (A–C) Retinal TEM sections. Compared with controls (A) bnch mutant photoreceptors (B) accumulate cytoplasmic inclusions. Inclusions are highlighted in transparent green (B) and quantified (C). Error bars indicate SEM. (D–F) Laminar TEM sections. Compared with controls (D) bnch mutant laminar cartridges (E) accumulate cytoplasmic inclusions. Inclusions are highlighted in green (E) and quantified (F). Error bars indicate SEM. Bars, 1 μm.
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fig3: Cytoplasmic membranous inclusions accumulate in the bnch mutant visual system. (A–C) Retinal TEM sections. Compared with controls (A) bnch mutant photoreceptors (B) accumulate cytoplasmic inclusions. Inclusions are highlighted in transparent green (B) and quantified (C). Error bars indicate SEM. (D–F) Laminar TEM sections. Compared with controls (D) bnch mutant laminar cartridges (E) accumulate cytoplasmic inclusions. Inclusions are highlighted in green (E) and quantified (F). Error bars indicate SEM. Bars, 1 μm.

Mentions: Previous studies have suggested a role for bnch in late endosomal/lysosomal membrane trafficking and neuromuscular synapse growth (Nakano et al., 2001; Sweeney and Davis, 2002). To examine the subcellular and developmental consequences of zygotic loss of bnch in the visual system, we performed transmission electron microscopy (TEM) studies of adult homozygous eyes. Because bnch escaper frequencies are generally low and escapers have a short life span, we used the eyFLP system to generate clones in the retina and the lamina (Fig. 3). In the retina we observed a large number of abnormal membranous inclusions in the cell bodies of mutant photoreceptors, while rhabdomere morphology was intact (Fig. 3, A and B). Compared with controls, bnch mutant photoreceptors displayed a 6–10-fold increase in the number of membranous cytoplasmic inclusions (Fig. 3 C).


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)

Cytoplasmic membranous inclusions accumulate in the bnch mutant visual system. (A–C) Retinal TEM sections. Compared with controls (A) bnch mutant photoreceptors (B) accumulate cytoplasmic inclusions. Inclusions are highlighted in transparent green (B) and quantified (C). Error bars indicate SEM. (D–F) Laminar TEM sections. Compared with controls (D) bnch mutant laminar cartridges (E) accumulate cytoplasmic inclusions. Inclusions are highlighted in green (E) and quantified (F). Error bars indicate SEM. Bars, 1 μm.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Cytoplasmic membranous inclusions accumulate in the bnch mutant visual system. (A–C) Retinal TEM sections. Compared with controls (A) bnch mutant photoreceptors (B) accumulate cytoplasmic inclusions. Inclusions are highlighted in transparent green (B) and quantified (C). Error bars indicate SEM. (D–F) Laminar TEM sections. Compared with controls (D) bnch mutant laminar cartridges (E) accumulate cytoplasmic inclusions. Inclusions are highlighted in green (E) and quantified (F). Error bars indicate SEM. Bars, 1 μm.
Mentions: Previous studies have suggested a role for bnch in late endosomal/lysosomal membrane trafficking and neuromuscular synapse growth (Nakano et al., 2001; Sweeney and Davis, 2002). To examine the subcellular and developmental consequences of zygotic loss of bnch in the visual system, we performed transmission electron microscopy (TEM) studies of adult homozygous eyes. Because bnch escaper frequencies are generally low and escapers have a short life span, we used the eyFLP system to generate clones in the retina and the lamina (Fig. 3). In the retina we observed a large number of abnormal membranous inclusions in the cell bodies of mutant photoreceptors, while rhabdomere morphology was intact (Fig. 3, A and B). Compared with controls, bnch mutant photoreceptors displayed a 6–10-fold increase in the number of membranous cytoplasmic inclusions (Fig. 3 C).

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