Human Molecular Genetics Advance Access originally published online on March 6, 2007
Human Molecular Genetics 2007 16(9):1007-1016; 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, 2 Department of Biochemistry and Biophysics and 3 Department 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, Box 645, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. Fax: +1 5855061972; Email: david_pearce{at}urmc.rochester.edu
Received December 22, 2006; 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 for Batten disease. Previous studies have suggested that synthesis and degradation of arginine are unaltered in btn1-. Using the yeast model for the Batten disease, we have determined that although 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 the 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- cells is detrimental and is suggestive that btn1- and perhaps mutation of CLN3 predispose cells to keep arginine levels lower than normal.
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  N. S. Osorio, A. Carvalho, A. J. Almeida, S. Padilla-Lopez, C. Leao, J. Laranjinha, P. Ludovico, D. A. Pearce, and F. Rodrigues Nitric Oxide Signaling Is Disrupted in the Yeast Model for Batten Disease Mol. Biol. Cell, July 1, 2007; 18(7): 2755 - 2767. [Abstract] [Full Text] [PDF]
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