22 April 2004. The clamp, the boot, whatever you call it, if you find one on your car you’ll appreciate how a seemingly small attachment can keep its wheels from turning. In today’s Sciencexpress, Ted and Valina Dawson and colleagues at Johns Hopkins University, Baltimore, Maryland, report that covalently clamping parkin with nitric oxide (NO)—a chemical reaction called S-nitrosylation—may stop this enzyme in its tracks. The results suggest a link between sporadic forms of Parkinson’s disease (PD), parkin, and chemical modification by NO, which has been implicated as a cause of neurodegeneration (for example, see ARF related news story).
While mutations that cripple the ubiquitin ligase activity of parkin are known to cause rare inherited forms of Parkinson’s (see ARF related news story), a pathological role for the protein in sporadic PD has been less forthcoming. But evidence linking oxidative stress to degeneration of the dopaminergic neurons that are affected by PD has been accumulating, and this prompted the Dawson lab to investigate if parkin can be poisoned by small oxidants, such as NO.
First author Kenny Chung and colleagues tested this theory by treating parkin-expressing kidney cells with S-nitrosoglutathione, a commonly used NO donor. Chung found that the parkin was indeed modified in these cells, while, in contrast, no modification occurred in the test tube. By testing some of the cellular lysate, Chung confirmed that S-nitrosylation of parkin was dependent on a heat-labile component, most likely a protein.
But is any of this relevant to Parkinson’s disease? It may be. Chung found that nitrosylation inactivates the ubiquitin ligase, but perhaps more importantly, he also found that compared to controls, global levels of nitrosylated protein are twofold higher in brain tissue samples from Parkinson’s victims. Specifically, Chung found measurable amounts of nitrosylated parkin in six of eight samples taken from patients with either PD or dementia with Lewy bodies (the latter shares some of the symptoms and pathology of Parkinson’s). In contrast, the authors did not find modified parkin in any of five control samples. “The results,” suggest the authors, “link parkin function with the more common sporadic form of Parkinson’s disease and the related α-synucleinopathy, DLB, through nitrosative and oxidative stress.”
In a commonly used animal model of PD, mitochondria are stressed with the chemical MPTP. Chung and colleagues found that parkin also gets nitrosylated in these animals. Using knockout mice, the authors showed that both neuronal nitric oxide synthase (NOS) and microglial-derived NOS are required for this modification. These findings, plus the recent discovery of a PD gene that codes for a mitochondrial protein (see ARF related news story), are sure to keep the debate about oxidative stress and neurodegeneration rolling along.
In keeping with the oxidative stress connection, researchers at the Parkinson’s Study Group revealed in Monday’s Archives of Neurology that rasagiline, a monoamine oxidase B (MAO B) inhibitor, appears effective in staving off some of the symptoms of Parkinson’s. The group used a delayed-start clinical trial—where some of the patients to receive the drug were first given placebo for six months—to test the drug’s effectiveness. The delayed-start cohort did not improve as much as did subjects who received the drug for a full year. Of 371 volunteers in early stages of Parkinson’s (none of whom were taking dopamine), the disease progressed more slowly in those who had taken the drug from the start of the trial. After a year, volunteers taking 2 mg of rasagiline per day had Unified Parkinson's Disease Rating Scale scores that were, on average, 2.29 units lower than those who had taken placebo for the first six months, then the same dose of the drug. The results were statistically significant (P = 0.01). In fact, those who took just 1 mg of the drug for the full year had better scores than those taking 2 mg per day after the delayed start. The study was conducted at 32 clinical sites in the U.S. and Canada. Preliminary trial results were first reported in December 2002 (see ARF related news story).
Rasagiline, not yet approved for use in PD (though its cousin selegiline is), slows the degradation of the neurotransmitter dopamine, which is oxidized by MAOs. However, MAOs also contribute to the generation of toxic reactive oxygen species (see ARF related news story), which may explain why results from some laboratories indicate the drug can also protect neurons from degeneration.—Tom Fagan.
Chung KK, Dawson TM, Thomas B, Li X, Pletnikova O, Troncoso JC, Marsh L, Dawson VL. S-Nitrosylation of parkin regulates ubiquitination and compromises parkin’s protective function. Sciencexpress 2004 April 22. Abstract
The Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch. Neurol. 2004 April 16;61:561-566. Abstract