title: Absence of Btn1p in the yeast model for juvenile Batten disease may cause arginine to become toxic to yeast cells.
abstract: Lymphoblast cell lines established from individuals with juvenile Batten disease (JNCL) bearing mutations in CLN3 and yeast strains lacking Btn1p (btn1-Delta), 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-Delta. Using the yeast model for the Batten disease, we have determined that although btn1-Delta 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-Delta), in combination with btn1-Delta, 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-Delta, but not wild-type cells. Therefore, elevation of intracellular levels of arginine in btn1-Delta cells is detrimental and is suggestive that btn1-Delta and perhaps mutation of CLN3 predispose cells to keep arginine levels lower than normal.
authors.affiliation: Center for Aging and Developmental Biology, Aab Institute of Biomedical Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Seasson Phillips
authors.initials: SP
authors.lastname: Vitiello
authors.forename: Devin M
authors.initials: DM
authors.lastname: Wolfe
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000235:genetics / Q000502:physiology; D001120:Arginine / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D050976:Basic-Leucine Zipper Transcription Factors; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D005816:Genetic Complementation Test; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D008954:Models, Biological; D018832:Molecular Chaperones / Q000235:genetics; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014617:Vacuoles / Q000378:metabolism
chemical_list: D026923:Amino Acid Transport Systems, Basic; D050976:Basic-Leucine Zipper Transcription Factors; C502212:CAN1 protein, S cerevisiae; C105199:CLN3 protein, human; D016213:Cyclins; D004268:DNA-Binding Proteins; C501391:GCN4 protein, S cerevisiae; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C489809:YHC3 protein, S cerevisiae; D001120:Arginine