Huntington’s Disease Could Stem From Cysteine Depletion

A repeating gene sequence that codes for a mutant protein in the DNA of patients with Huntington’s disease is to blame for the disorder, but how this genetic mutation causes neurodegeneration has long stymied scientists. Now a team of medical researchers led by Solomon H. Snyder at Johns Hopkins University is proposing a cellular mechanism for the disease (Nature 2014, DOI: 10.1038/nature13136).

Snyder’s theory—that the disease symptoms stem from a lack of the amino acid cysteine in the brain—is based on experiments with cultured human tissue and with mice that suffer symptoms of the disease. If proven to extend to humans in clinical trials, the theory could “decrease the onset of Huntington’s disease symptoms with a simple dietary supplementation,” comments Gavril W. Pasternak, a neuropharmacologist at Memorial Sloan Kettering Cancer Center, in New York City.

“It would be a major milestone in the understanding and treatment of the neurodegenerative disease,” Pasternak says, and would eliminate the need for “complex and risky” genetic therapy approaches that are currently the disease’s most promising treatment.

Huntington’s disease symptoms usually begin midlife, with cognitive problems, increasing loss of muscle coordination, and then dementia. Life expectancy is reduced to about 20 years after onset.

Researchers have long tried to pinpoint what the mutant Huntington’s disease protein does to brain cells but to date have only found evidence that it influences transcription. Snyder’s team showed that this mutant protein binds a transcription factor required to produce an enzyme called cystathionine γ-lyase (CSE), thus depleting the enzyme’s levels in brain cells.

Because CSE catalyzes a crucial step in the biosynthesis of cysteine, the mutation leads to an overall depletion of cysteine in brain cells. When the researchers supplemented Huntington’s mouse models with cysteine, they could reverse the disease’s characteristics.

“Since the disease is based on a very discrete genetic abnormality, the mouse model is very good,” suggesting the results could apply to humans, Snyder says. “But it makes me nervous to get people’s hopes up. We won’t know if this is a successful therapy until it is tested in clinical trials,” he cautions.