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A more recent version of this article appeared on March 1, 2004
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Submitted on February 28, 2003
Revised on October 20, 2003
Accepted on October 23, 2003
1 Cambridge Institute for Medical Research and Department of Clinical Biochemistry, University of Cambridge, Hills Road, Cambridge CB2 2XY, UK
2 David Geffen School of Medicine at University of California, Los Angeles, California 90095-7088
3 Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QJ
* Corresponding author. E-mail address: jpl10{at}cam.ac.uk.
Batten disease is a neurodegenerative disorder resulting from mutations in CLN3, a polytopic membrane protein, whose predominant intracellular destination in nonneuronal cells is the lysosome. The topology of CLN3 protein, its lysosomal targeting mechanism, and the development of Batten disease are poorly understood. We provide experimental evidence that both the N- and C-termini and one large loop domain of CLN3 face the cytoplasm. We have identified two lysosomal targeting motifs which mediate the sorting of CLN3 in transfected nonneuronal and neuronal cells: an unconventional motif in the long C-terminal cytosolic tail consisting of a methionine and a glycine separated by nine amino acids [ M(X)9G] , and a more conventional dileucine motif, located in the large cytosolic loop domain and preceded by an acidic patch. Each motif on its own was sufficient to mediate lysosomal targeting, but optimal efficiency required both. Interestingly, in primary neurons, CLN3 was prominently seen both in lysosomes in the cell body and in EEA1-containing endosomes along neuronal processes. As there are few lysosomes in axons and peripheral parts of dendrites, the presence of CLN3 in endosomes of neurones may be functionally important. Endosomal association of the protein was independent of the two lysosomal targeting motifs.
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