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Published 5 July 2005. doi:10.1083/jcb.200412001
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 1, 127-139
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Article

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

Bart Dermaut1, Koenraad K. Norga1,2,4,5, Artur Kania1, Patrik Verstreken1, Hongling Pan1, Yi Zhou1, Patrick Callaerts4, and Hugo J. Bellen1,2,3

1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030
2 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030
3 Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030
4 Laboratory of Developmental Genetics, Flanders Interuniversity Institute of Biotechnology (VIB), University of Leuven, B-3000 Leuven, Belgium
5 Division of Pediatrics, University of Leuven, School of Medicine, B-3000 Leuven, Belgium

Correspondence to Hugo J. Bellen: hbellen{at}bcm.tmc.edu

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.

B. Dermaut and K.K. Norga contributed equally to this paper.

A. Kania's present address is Institut de Recherches Cliniques de Montreal, Avenue des Pins Ouest 110, Montréal H2W 1R7, Québec, Canada.

Abbreviations used in this paper: ACS, anion/cation subfamily; bnch, benchwarmer gene; EJP, excitatory junctional potential; ERG, electroretinogram; LSD, lysosomal storage disorder; MFS, major facilitator superfamily; MVB, multivesicular bodies; NMJ, neuromuscular junction; RP, reserve pool; RRP, readily releasable pool; TEM, transmission electron microscopy; PAS, periodic acid Schiff.


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