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Human Molecular Genetics Advance Access originally published online on October 26, 2005
Human Molecular Genetics 2005 14(23):3759-3773; doi:10.1093/hmg/ddi406
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Defective lysosomal arginine transport in juvenile Batten disease

Denia Ramirez-Montealegre1 and David A. Pearce1,2,3,*

1Center for Aging and Developmental Biology, Aab Institute of Biomedical Sciences, 2Department of Biochemistry and Biophysics and 3Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA

* To whom correspondence should be addressed at: Center for Aging and Developmental Biology, Department of Biochemistry and Biophysics, PO Box 645, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14642, USA. Tel: +1 5852731514; Fax: +1 5852761972; Email: david_pearce{at}urmc.rochester.edu

Received August 12, 2005; Accepted October 20, 2005

Mutations in the CLN3 gene, which encodes a lysosomal membrane protein, are responsible for the neurodegenerative disorder juvenile Batten disease. A previous study on the yeast homolog to CLN3, designated Btn1p, revealed a potential role for CLN3 in the transport of arginine into the yeast vacuole, the equivalent organelle to the mammalian lysosome. Lysosomes isolated from lymphoblast cell lines, established from individuals with juvenile Batten disease-bearing mutations in CLN3, but not age-matched controls, demonstrate defective transport of arginine. Furthermore, we show that there is a depletion of arginine in cells derived from individuals with juvenile Batten disease. We have, therefore, characterized lysosomal arginine transport in normal lysosomes and show that it is ATP-, v-ATPase- and cationic-dependent. This and previous studies have shown that both arginine and lysine are transported by the same transport system, designated system c. However, we report that lysosomes isolated from juvenile Batten disease lymphoblasts are only defective for arginine transport. These results suggest that the CLN3 defect in juvenile Batten disease may affect how intracellular levels of arginine are regulated or distributed throughout the cell. This assertion is supported by two other experimental approaches. First, an antibody to CLN3 can block lysosomal arginine transport and second, expression of CLN3 in JNCL cells using a lentiviral vector can restore lysosomal arginine transport. CLN3 may have a role in regulating intracellular levels of arginine possibly through control of the transport of this amino acid into lysosomes.


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