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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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Loss of bnch enhances tau neurotoxicity in a dose-dependent manner. (A and B) Eyes that express one copy of GMR-htau4R (A) or lack bnch (B) appear morphologically normal. (C and D) Removal of one copy of bnch in eyes expressing one copy of GMR-htau4R induces a mild rough eye phenotype (C), whereas overexpression of one of GMR-htau4R copy in a bnch  background results in a small and rough eye (D).
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fig9: Loss of bnch enhances tau neurotoxicity in a dose-dependent manner. (A and B) Eyes that express one copy of GMR-htau4R (A) or lack bnch (B) appear morphologically normal. (C and D) Removal of one copy of bnch in eyes expressing one copy of GMR-htau4R induces a mild rough eye phenotype (C), whereas overexpression of one of GMR-htau4R copy in a bnch background results in a small and rough eye (D).

Mentions: To test the possibility of whether defective lysosomal function due to loss of bnch is able to trigger tauopathy, we used a reported tauopathy fly model that expresses the longest four repeat isoform of human wild-type tau in the eye (GMR-htau4R) (Jackson et al., 2002). This model behaves as a genetically sensitized system that allows the identification of genetic modifiers of tau-mediated neurodegeneration by assessing roughening of the eye as a quantitative readout of tau toxicity. We combined this model with the eyFLP system to generate homozygous bnch eyes that simultaneously express one copy of the GMR-htau4R transgene and compared such eyes with several controls. As shown in Fig. 9, eyes that express either one copy of GMR-htau4R (Fig. 9 A) or that are homozygous bnch mutant (Fig. 9 B) display no obvious roughening. However, removal of one (Fig. 9 C) or two copies (Fig. 9 D) of bnch in eyes expressing one copy of GMR-htau4R induced a moderate and very severe rough eye phenotype, respectively. These results indicate that loss of bnch can dose-dependently enhance tau toxicity and suggest that lysosomal dysfunction is a potent trigger of tau toxicity in Drosophila.


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)

Loss of bnch enhances tau neurotoxicity in a dose-dependent manner. (A and B) Eyes that express one copy of GMR-htau4R (A) or lack bnch (B) appear morphologically normal. (C and D) Removal of one copy of bnch in eyes expressing one copy of GMR-htau4R induces a mild rough eye phenotype (C), whereas overexpression of one of GMR-htau4R copy in a bnch  background results in a small and rough eye (D).
© Copyright Policy
Related In: Results  -  Collection

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

fig9: Loss of bnch enhances tau neurotoxicity in a dose-dependent manner. (A and B) Eyes that express one copy of GMR-htau4R (A) or lack bnch (B) appear morphologically normal. (C and D) Removal of one copy of bnch in eyes expressing one copy of GMR-htau4R induces a mild rough eye phenotype (C), whereas overexpression of one of GMR-htau4R copy in a bnch background results in a small and rough eye (D).
Mentions: To test the possibility of whether defective lysosomal function due to loss of bnch is able to trigger tauopathy, we used a reported tauopathy fly model that expresses the longest four repeat isoform of human wild-type tau in the eye (GMR-htau4R) (Jackson et al., 2002). This model behaves as a genetically sensitized system that allows the identification of genetic modifiers of tau-mediated neurodegeneration by assessing roughening of the eye as a quantitative readout of tau toxicity. We combined this model with the eyFLP system to generate homozygous bnch eyes that simultaneously express one copy of the GMR-htau4R transgene and compared such eyes with several controls. As shown in Fig. 9, eyes that express either one copy of GMR-htau4R (Fig. 9 A) or that are homozygous bnch mutant (Fig. 9 B) display no obvious roughening. However, removal of one (Fig. 9 C) or two copies (Fig. 9 D) of bnch in eyes expressing one copy of GMR-htau4R induced a moderate and very severe rough eye phenotype, respectively. These results indicate that loss of bnch can dose-dependently enhance tau toxicity and suggest that lysosomal dysfunction is a potent trigger of tau toxicity in Drosophila.

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