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Nitric Oxide Signaling Is Disrupted in the Yeast Model for Batten Disease

2007; American Society for Cell Biology; Volume: 18; Issue: 7 Linguagem: Inglês

10.1091/mbc.e06-11-1053

1939-4586

Nuno S. Osório, Agostinho Carvalho, Agostinho J. Almeida, Sergio Padilla-López, Cecı́lia Leão, João Laranjinha, Paula Ludovico, David A. Pearce, Fernando Rodrigues,

Parkinson's Disease Mechanisms and Treatments

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-Δ) that lacks BTN1, the homologue to human CLN3, has increased resistance to menadione-generated oxidative stress. Expression of human CLN3 complemented the btn1-Δ phenotype, and equivalent Btn1p/Cln3 mutations correlated with JNCL severity. We show that the previously reported decreased levels of l-arginine in btn1-Δ 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-Δ 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.