BY TOM VALEO
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.”
See what Huntington’s disease specialists had to say about this research in the May 1 issue of Neurology Today. Read our previous stories on Huntington’s disease here.