Emory Report

September 5, 2000

 Volume 53, No. 2

Li finds clues to understanding Huntington's disease

By Holly Korschun

Scientists in the School of Medicine have discovered that fragments of mutant proteins associated with Huntington's disease, although widely expressed throughout the body, kill only certain neurons within the brain.

The research, conducted by Emory neurogeneticist Xiao-Jiang Li and his colleagues, was published in the August issue of Nature Genetics.

Huntington's is an inherited, progressive, neurodegenerative disorder that currently affects 30,000 Americans. It is characterized by movement disorders, psychiatric complications and dementia. An additional 150,000 individuals are at a 50 percent risk of inheriting the gene responsible for the disease. There is no cure or effective treatment for Huntington's.

Although the exact mechanism of Huntington's is unknown, scientists know it originates with a type of genetic mistake in the gene encoding for the huntingtin protein. As a result of this mutation, the mutant protein carries an elongated repeat of the amino acid glutamine.

Although the mutant huntingtin protein is widely expressed throughout the body, including large organs like the heart and liver, it appears to cause the loss and dysfunction of only certain neurons in the areas of the brain affecting cognitive function and movement coordination.

The mutant huntingtin protein is not toxic to cells unless it is cleaved and degraded into smaller fragments that contain an elongated repeat, at which point it becomes lethal to cells and forms aggregates.

Aggregates of mutant huntingtin protein have been used as pathological markers for these toxic protein fragments ever since scientists discovered them several years ago in the Huntington's brain. The exact role they play in the disease is still widely debated, Li said.

Some scientists believe aggregates are a byproduct of the disease and could have a protective effect by absorbing all the mutant protein together and thus reducing toxicity, while others think aggregates are the cause of Huntington's.

What mystifies scientists is why the mutant proteins kill only neurons and not other cells, and why, although aggregates are present in many neurons, only certain neurons die.

In collaboration with Peggy Shelbourne of the University of Glasgow, He Li, a postdoctoral fellow in Xiao-Jiang Li's group, discovered that not only are large aggregates of mutant proteins present in the nuclei of certain neuronal cells, but also that tiny aggregates are present in the axon terminals of cells corresponding to the brain regions specifically affected by Huntington's.

Axons are spiny extensions of neurons that carry brain impulses. They contain small vesicles that store neurotransmitters and release them when a neuron is stimulated or excited, thus these vesicles are very important in neuronal communication.

Li and his colleagues found that mutant huntingtin fragments affect the storage of neurotransmitters in the vesicles. The fragments of mutant proteins or their aggregates are likely to block the vesicles in the axons and thus inhibit the release of neurotransmitters.

"Our finding, that the mutant huntingtin proteins are selectively accumulated and aggregated in those neurons affected by Huntington's disease, may mean that those neurons have specific enzymes or proteins that create a favorable environment for the accumulation of toxic mutant protein fragments that affect neuronal communication," Li said. "If that is the case, drugs might be developed to target those specific enzymes or proteins [and] prevent the degradation or cleavage that causes the toxic fragments to form and accumulate in the brain."

Li believes the finding also has implications for other neurodegenerative diseases resulting from similar triple-repeat genetic mutations.

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