Human Molecular Genetics Advance Access published online on March 6, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm046
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Absence of Btn1p in the yeast model for juvenile Batten disease may cause arginine to become toxic to yeast cells
1 Center for Aging and Developmental Biology, Aab Institute of Biomedical Sciences, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642 2 Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642 3 Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
* Correspondence should be addressed to: Center for Aging and Developmental Biology, Box 645, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642. E-mail: David_Pearce{at}urmc.rochester.edu; Fax: 585-506-1972
Received December 22, 2006; Revised February 26, 2007; Accepted February 26, 2007
Lymphoblast cell lines established from individuals with juvenile Batten disease (JNCL) bearing mutations in CLN3 and yeast strains lacking Btn1p (btn1-
), the homolog to CLN3, have decreased intracellular levels of arginine and defective lysosomal/vacuolar transport of arginine. It is important to establish the basis for this decrease in arginine levels and whether restoration of arginine levels would be of therapeutic value in Batten disease. Previous studies have suggested that synthesis and degradation of arginine are unaltered in btn1-. Using the yeast model for Batten disease, we have determined that while btn1- results in decreased intracellular arginine levels, it does not result from altered arginine uptake, arginine efflux or differences in arginine incorporation into peptides. However, expression of BTN1 is dependent on arginine and Gcn4p, the master regulator of amino acid biosynthesis. Moreover, deletion of GCN4 (gcn4-), in combination with btn1-, results in a very specific growth requirement for arginine. In addition, increasing intracellular levels of arginine through overexpression of Can1p, the plasma membrane basic amino acid permease, results in increased cell volume and a severe growth defect specific to basic amino acid availability, for btn1-, but not wild type cells. Therefore, elevation of intracellular levels of arginine in btn1- yeast cells is detrimental and is suggestive that btn1- and perhaps mutation of CLN3 predisposes cells to keep arginine levels lower than normal.
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