Cause of neurodegeneration in Huntington's disease discovered

The severe neurodegeneration associated with Huntington's disease may result from molecular mutations that block the transport of nutrients within cells.

Findings from the Emory University School of Medicine indicate that the mutant huntingtin protein limits the efforts of the huntingtin-associated protein-1 (HAP1) to provide nutrients to growing neurons, or neurites. Without those nutrients, neurites fail to develop and mature neurons degenerate.

Huntington's disease was first identified more than 125 years ago, and often inhibits speech, movement, reasoning and memory. The result of an abnormal Huntington gene, the hereditary disorder is estimated to affect one out of every 10,000 people. Though some current pharmacological treatments do address symptoms, scientists have been unable to stop the disease's progression.

However, scientists at Emory are making headway in the search for a cure. The findings that appear in the Journal of Neuroscience are the latest of more than a decade of Huntington's disease-related discoveries led by Xiao-Jiang Li, PhD, professor of human genetics at Emory University School of Medicine.

Juan Rong, doctoral student in the neuroscience graduate program at the Emory University School of Medicine, is the lead author of the article. The senior author, Dr. Li, first discovered the protein HAP1 as a postdoctoral fellow in 1995. In previous articles, he has identified the importance of HAP1 to the normal functioning of the hypothalamus, a region of the brain that acts as a central switchboard to regulate feeding and other body functions. Earlier this year, Dr. Li's group published an article identifying HAP1Us role connecting insulin to the hypothalamus in the journal Nature Medicine.

"This protein is very important," says Dr. Li. "When an animal does not have HAP1 it dies after birth. Certainly, it's essential for differentiation and survival of some neurons in the brain."

In this latest paper, Dr. Li, Ms. Rong, and their colleagues used cellular models to show that HAP1 normally links to transport proteins, including the growth factor receptor tyrosine kinase (TrkA), in growing neurites. HAP1 protects TrkA from degrading, ensuring the neurites continue to develop. This trafficking function is regulated by the addition of phosphate and oxygen to the HAP1 protein, a process known as phosphorylation.

However, when mutant huntingtin is present, the Emory researchers have found that this disease protein stops HAP1 from fulfilling its trafficking function. HAP1 cannot prevent the degradation of TrkA. The insufficient amount of TrkA cannot maintain the normal function of nerve terminals.

Although the discovery that HAP1 works as a transporter and plays a crucial role in neuronal function was obtained from cell models, it will assist scientists as they continue to look for a cure for Huntington's disease. Dr. Li's current experiments involve selective HAP1 deletions from neurons in animal models, and his results are sure to offer relevant clues to the mechanisms behind Huntington's disease.

Says Dr. Li, "If we can find the pathogenesis for Huntington's disease, or if we know how the mutant huntingtin affects the transporting inside cells, maybe then we can find some effective treatment to prevent this kind of defect."

Research into other neurodegenerative disorders may also benefit from a thorough understanding of HAP1. "This work also has implications for understanding the normal physiological processing for neuronal functioning," says Dr. Li.