NO Parkin in Parkinson's Disease

Abstract

In their report “S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function” (28 May, p. 1328; Science Express 22 Apr.), K. K. K. Chung et al. raise the intriguing possibility that nitric oxide (NO) may contribute to the degenerative process in Parkinson's disease (PD). Unfortunately, the data shed no light on the central question, which is whether S-nitrosation of parkin attenuates its protective activity in vivo. That covalent modification of a cysteine residue(s) of a protein with unphysiological amounts of chemical reagent [0.1 mM S-nitroso-glutathione or NO donor] can decrease activity is not surprising and is biologically uninformative. A similarly unphysiological effect can occur when NO-synthase-containing cells are stimulated with ionophore in culture. The question is whether the amount of NO produced is similar to that produced in vivo. The identification of S-nitrosated parkin in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MTPT)-treated mice and human patients is suggestive, but some degree of modification would be expected in diseased tissue; the critical question is whether a high enough fraction of parkin is nitrosated to decrease its protective action. Unfortunately, no information is provided for this crucial point. It would be informative, for example, to test whether addition of ascorbate, which would presumably reduce nitrosothiol and regenerate thiol, increases parkin activity in samples from MTPT-treated mice and human tissue.