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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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Lysosomes and MVBs in the bnch mutant visual system. (A–D) TEM sections through bnch mutant eyes. (A) Multilammellar onion-like structure with morphologically heterogeneous content in a laminar bnch mutant glial cell (bar, 0.2 μm). (B) MVBs (arrows) in a bnch mutant retinal photoreceptor (bar, 0.2 μm). (C and D) Multilammellar bodies (arrows) are present in a presynaptic photoreceptor terminal (C) as well as a postsynaptic laminar monopolar cell (D).
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fig4: Lysosomes and MVBs in the bnch mutant visual system. (A–D) TEM sections through bnch mutant eyes. (A) Multilammellar onion-like structure with morphologically heterogeneous content in a laminar bnch mutant glial cell (bar, 0.2 μm). (B) MVBs (arrows) in a bnch mutant retinal photoreceptor (bar, 0.2 μm). (C and D) Multilammellar bodies (arrows) are present in a presynaptic photoreceptor terminal (C) as well as a postsynaptic laminar monopolar cell (D).

Mentions: The membranous cytoplasmic inclusions are morphologically highly heterogeneous and vary in size from 0.2 to 2.5 μm (Fig. 4). One population of inclusions contains multilayered membranes often together with partially degraded organelles or other cytoplasmic constituents (Fig. 4 A). Most likely these structures correspond to secondary lysosomes in the phase of digesting endosomal and/or autophagic cargo. This heterogeneous population of secondary lysosomes was observed in retinal photoreceptor cell bodies (Fig. 3 B) and laminar glial cells (Fig. 3 E and Fig. 4 A). In the bnch mutant lamina, these multilamellar structures were also found in presynaptic photoreceptor projections as well as postsynaptic monopolar cells (Fig. 4, C and D).


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)

Lysosomes and MVBs in the bnch mutant visual system. (A–D) TEM sections through bnch mutant eyes. (A) Multilammellar onion-like structure with morphologically heterogeneous content in a laminar bnch mutant glial cell (bar, 0.2 μm). (B) MVBs (arrows) in a bnch mutant retinal photoreceptor (bar, 0.2 μm). (C and D) Multilammellar bodies (arrows) are present in a presynaptic photoreceptor terminal (C) as well as a postsynaptic laminar monopolar cell (D).
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Related In: Results  -  Collection

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

fig4: Lysosomes and MVBs in the bnch mutant visual system. (A–D) TEM sections through bnch mutant eyes. (A) Multilammellar onion-like structure with morphologically heterogeneous content in a laminar bnch mutant glial cell (bar, 0.2 μm). (B) MVBs (arrows) in a bnch mutant retinal photoreceptor (bar, 0.2 μm). (C and D) Multilammellar bodies (arrows) are present in a presynaptic photoreceptor terminal (C) as well as a postsynaptic laminar monopolar cell (D).
Mentions: The membranous cytoplasmic inclusions are morphologically highly heterogeneous and vary in size from 0.2 to 2.5 μm (Fig. 4). One population of inclusions contains multilayered membranes often together with partially degraded organelles or other cytoplasmic constituents (Fig. 4 A). Most likely these structures correspond to secondary lysosomes in the phase of digesting endosomal and/or autophagic cargo. This heterogeneous population of secondary lysosomes was observed in retinal photoreceptor cell bodies (Fig. 3 B) and laminar glial cells (Fig. 3 E and Fig. 4 A). In the bnch mutant lamina, these multilamellar structures were also found in presynaptic photoreceptor projections as well as postsynaptic monopolar cells (Fig. 4, C and D).

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