Mutant Proteins Selectively Accumulate In Neurons Affected By Huntington's Disease

The research, conducted by Emory neurogeneticist Xiao-Jiang Li, Ph.D., and his colleagues, was published in the August 2000 issue of the journal Nature Genetics.

Huntington's is an inherited, progressive, neurodegenerative disorder that currently affects 30,000 Americans. The disease is characterized by movement disorders, psychiatric complications and dementia. An additional 150,000 individuals are at a 50% risk of inheriting the gene that is 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 that it originates with a type of genetic mistake called a CAG triple repeat expansion in the gene encoding for the huntingtin protein. CAG encodes for the amino acid called glutamine. As a result of this mutation, the mutant protein carries an elongated glutamine repeat. 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 striatum and cortex of the brain -- areas that affect 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 the cells and forms aggregates. In humans, the mutant fragments clump together to form aggregates and affect certain types of neurons. Aggregates of mutant huntingtin protein have been used as a pathological marker for these toxic protein fragments ever since scientists discovered several years ago that aggregates from these mutant proteins form in neurons in the Huntington's brain.

The exact role that aggregates play in Huntington's disease is still widely debated, says Dr. Li. 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.

Scientists have been mystified, however, by 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, Ph.D., at the University of Glasgow, He Li, Ph.D., a postdoctoral fellow in Dr. 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 of mutant protein fragments are present in the axon terminals of cells corresponding to the brain region and neurons specifically affected by Huntington's disease.

Axons are spiny extensions of neurons that carry brain impulses away from neurons and toward other cells. The axons 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. Dr. 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," explains Dr. Li. "If that is the case, drugs might be developed to target those specific enzymes or proteins to prevent the degradation or cleavage that causes the toxic fragments to form and accumulate in the brain."

Dr. Li's group is currently using mouse models for Huntington's that develop aggregates in neurons that do not show obvious neurodegeneration, but that eventually lead to behavioral and movement disorders. This demonstrates that the toxic huntingtin fragments are produced before any symptoms are present, he says, which should be an important indicator of early pathological events in Huntington's and elucidate a target for therapeutic strategies.

Dr. Li believes the finding that mutant protein fragments selectively accumulate in certain neurons also has implications for other neurodegenerative diseases resulting from similar triple-repeat genetic mutations.

His research is supported by grants from the National Institutes of Health, the Hereditary Disease Foundation and the Huntington's Disease Society of America.