ARTICLE IN BRIEF
Researchers found reduced levels of cystathionine gamma lyase in animal models of Huntington's disease (HD) and in the postmortem tissue of patients with HD. Adding cysteine to the diet of HD mice delayed onset of motor abnormalities, such as hind limb clasping, poor rotarod performance, and weak grip strength; increased survival; and partially reversed decreases in brain weight and striatal volume.
Scientists at Johns Hopkins University School of Medicine have identified the elusive mechanism that might be responsible for the jerky movements, unsteady gait, and cognitive and psychiatric problems of Huntington's disease (HD), an autosomal genetic disorder that usually emerges in adulthood.
Working with mouse models of HD, the scientists found that mutant huntingtin protein interrupts the transcription of specificity protein 1 (Sp1), the transcriptional activator of cystathionine gamma lyase (CSE), an enzyme that contributes to the synthesis of the amino acid cysteine from cystathionine. The lack of CSE contributes to the oxidative stress and mitochondrial dysfunction found in the HD brain, they reported in the March 26 online edition of Nature.
The researchers found decreased levels of CSE in the striatum, hippocampus, hypothalamus, and brainstem of the HD mice. In postmortem tissue from human HD patients, they found CSE levels were profoundly reduced in the striatum and moderately reduced in the cerebral cortex, but not in the cerebellum. The amount of depletion of CSE correlated with severity of Huntington's disease. They also looked at CSE levels in postmortem tissue from patients with other neurodegenerative diseases, and found that the CSE was not reduced in brain tissue from patients with amyotrophic lateral sclerosis, multiple sclerosis, or spinocerebellar ataxia (SCA), even though SCA, like HD, results from a mutant gene that contains too many CAG repeats.
Adding cysteine to the diet of HD mice delayed onset of motor abnormalities, such as hind limb clasping, poor rotarod performance, and weak grip strength; increased survival; and partially reversed decreases in brain weight and striatal volume.
WHAT PROMPTED THE RESEARCH
The research began when first author Bindu Diana Paul, PhD, a molecular neuroscientist in the laboratory of Solomon H. Snyder, MD, in the department of neuroscience at Johns Hopkins University School of Medicine, noticed that the CSE knockout mice she had been studying behaved like HD mice when she picked them up. Instead of struggling to get free like normal mice, they clasped their hind paws together, which suggested a neurological deficit.
Few people had studied CSE in the brain, so Dr. Snyder and Dr. Paul investigated and found that CSE was lower than normal in HD mice and humans with the disease. They found that mutant huntingtin protein was binding to the transcription factor that turned the CSE gene on or off, which resulted in depletion of CSE and, presumably, of cysteine.
The findings could have clinical implications, Dr. Snyder told Neurology Today. “This work implies that the loss of CSE may be a major cause of neurologic disability, and that replacing the missing cysteine with N-acetylcysteine (a precursor of cysteine) might be therapeutic,” he said. “N-acetylcysteine is an antioxidant that people have been taking for many years.”
A phase 3 clinical trial is already under way to test the ability of creatine, another dietary supplement, to alleviate the symptoms of Huntington's disease.
“I think dietary supplements have great potential,” said Steven M. Hersch, MD, PhD, professor of neurology at Massachusetts General Hospital (MGH) and Harvard Medical School, who is the principal investigator of a phase 3 trial of creatine. “There are phase 3 trials going on for creatine, which reduces oxidative stress, and for Coenzyme Q10, an antioxidant, which has been shown in animal models to be neuroprotective,” said Dr. Hersch, director of the Laboratory of Neurodegeneration and Neurotherapeutics at MassGeneral Institute for Neurodegenerative Disease; and director of the New England HDSA Center of Excellence for Huntington's Disease at MGH.
Merit E. Cudkowicz, MD, Julieanne Dorn professor of neurology at Massachusetts General Hospital, is the principal investigator of the CoQ10 trial.
A decade ago Dr. Hersch and his colleagues investigated the possibility that cysteine might be neuroprotective in HD mice. In a paper published in the Journal of Neurochemistry they reported that cystamine increased levels of the antioxidant L-cysteine, and proposed it might be neuroprotective in HD.
“We noticed that cystamine elevated cysteine dramatically, and we speculated that might be an important mechanism of action,” Dr. Hersch said. “However, other neuroprotective mechanisms have also been proposed. It's nice to see further evidence for cysteine being relevant as a possible molecular basis for its depletion. I think this new paper extends the prior studies, helps validate cysteine levels as a therapeutic target, and confirms that oxidative stress and antioxidant strategies are compelling in HD.”
The mutation in the gene for huntingtin protein produces an array of downstream effects including oxidative damage, transcriptional dysregulation, energy deficits, and impaired proteolysis, which might lend themselves to therapeutic interventions, according to Dr. Hersch.
“Those mechanisms have a lot of science behind them and have potential therapies attached to them,” he said. “What's really interesting is why there are so many that seem significant based on studies of HD models. I guess the reason for that is that huntingtin interacts with so many different proteins and biochemical systems. It has many functions, some potentially toxic.”
M. Flint Beal, MD, FAAN, professor of neurology and neuroscience at Weill Medical College of Cornell University, has been investigating the role of oxidative damage in HD for more than two decades, as well as the potential of dietary interventions for HD, including CoQ10 and creatine, to alleviate symptoms.
“We started out back in 1980s before the gene had been identified,” he said.
The Nature paper “adds another potential cause of oxidative stress and damage,” he added. “I don't think anyone was aware that there was deficit in cysteine or hydrogen sulfide. It's a nicely done paper.”
Now he would like to see someone look for alterations in cysteine and glutathione in the spinal fluid of HD patients.
“You can actually measure glutathione in living patients with NMR (nuclear magnetic resonance) spectroscopy,” he said. “If there is disease, you should be able to see a decrease in the striatum. That would be very interesting. Then you could go back and treat with cysteine or inositol cysteine and see if that restored levels, and see what happens. You could probably run a small phase 2 clinical trial with a small number of patients and get an answer. It wouldn't be cheap, but compared to running a full-scale phase 3 trial, the cost would be trivial.”
A clinical trial that tests the ability of cysteine and its precursor, N-acetylcysteine, to alter the course of HD also would be interesting, said Andrew Feigin, MD, a professor of molecular medicine and neurology, and director of the Experimental Therapeutics Unit at the Susan and Leonard Feinstein Center for Neurosciences at the LIJ-North Shore Feinstein Institute for Medical Institute.
“The mechanism behind the gene mutation causes a decrease in transcription of the enzyme cystathionine gamma lyase, leading to decreased production of cysteine, ultimately resulting in increased oxidative stress and cell death,” said Dr. Feigin, who serves on the editorial advisory board of Neurology Today. “The transgenic animal models of Huntington's disease treated with cysteine and N-acetylcysteine seem to live longer and don't develop symptoms as early, which is very encouraging.”
CSE DEFICIENCY IN HUNTINGTON'S: WHAT THE EXPERTS THINK
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•. Paul BD, Sbodio JI, Xu R, Vandiver MS, Cha JY, Snowman AM, Snyder SH. Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington's disease. Nature 2014; E-pub 2014 March 26.
•. Fox JH, Barber DS, Singh B, Zucker B, Swindell MK, Norflus F, Buzescu R, Chopra R, Ferrante RJ, Kazantsev A, Hersch SM. Cystamine increases L-cysteine levels in Huntington's disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation. J Neurochem