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Vol. 18, Issue 7, 2755-2767, July 2007
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*Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710 Braga, Portugal; Center for Aging and Developmental Biology, Aab Institute of Biomedical Sciences, and Departments of Biochemistry and Biophysics and Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and Faculty of Pharmacy and Center for Neurosciences and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal
Submitted November 29, 2006;
Revised April 13, 2007;
Accepted April 19, 2007
Monitoring Editor: Thomas Fox
The juvenile form of neuronal ceroid lipofuscinoses (JNCLs), or Batten disease, results from mutations in the CLN3 gene, and it is characterized by the accumulation of lipopigments in the lysosomes of several cell types and by extensive neuronal death. We report that the yeast model for JNCL (btn1-
) that lacks BTN1, the homologue to human CLN3, has increased resistance to menadione-generated oxidative stress. Expression of human CLN3 complemented the btn1- phenotype, and equivalent Btn1p/Cln3 mutations correlated with JNCL severity. We show that the previously reported decreased levels of L-arginine in btn1- limit the synthesis of nitric oxide (·NO) in both physiological and oxidative stress conditions. This defect in ·NO synthesis seems to suppress the signaling required for yeast menadione-induced apoptosis, thus explaining btn1- phenotype of increased resistance. We propose that in JNCL, a limited capacity to synthesize ·NO directly caused by the absence of Cln3 function may contribute to the pathology of the disease.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
These authors contributed equally to this work.
Address correspondence to: Fernando Rodrigues (frodrigues{at}ecsaude.uminho.pt)
Abbreviations used: ANP, D-(–)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol; JNCL, juvenile neuronal ceroid lipofuscinose; L-NAME, nitro-L-arginine methyl ester; NCL, neuronal ceroid lipofuscinose; ·NO, nitric oxide; NOS, nitric-oxide synthase; ROS, reactive oxygen species.
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  S. P. Vitiello, J. W. Benedict, S. Padilla-Lopez, and D. A. Pearce Interaction between Sdo1p and Btn1p in the Saccharomyces cerevisiae model for Batten disease Hum. Mol. Genet., March 1, 2010; 19(5): 931 - 942. [Abstract] [Full Text] [PDF]
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R. I. Tuxworth, V. Vivancos, M. B. O'Hare, and G. Tear Interactions between the juvenile Batten disease gene, CLN3, and the Notch and JNK signalling pathways Hum. Mol. Genet., February 15, 2009; 18(4): 667 - 678. [Abstract] [Full Text] [PDF]
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B. Almeida, S. Buttner, S. Ohlmeier, A. Silva, A. Mesquita, B. Sampaio-Marques, N. S. Osorio, A. Kollau, B. Mayer, C. Leao, et al. NO-mediated apoptosis in yeast J. Cell Sci., September 15, 2007; 120(18): 3279 - 3288. [Abstract] [Full Text] [PDF]
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