The mutant gene associated with Huntington's disease does express a protein, according to researchers from the School of Medicine -- and that protein is associated with very specific components of a living cell.
Since the discovery two years ago of the gene associated with Huntington's disease (named IT15, located on chromosome 4), researchers worldwide have not been certain whether it does or does not express a protein. Thus it was not clear whether Huntington's disease is caused by knocking out the protein or by altering its function, although the latter explanation had seemed the most likely.
Genes carry out all their tasks through proteins, so confirming the presence of the mutant protein, named huntingtin, and learning more about its function became priorities for Huntington's disease researchers.
The Emory team, led by neurologist Steven M. Hersch, identified in tissue samples taken from patients with Huntington's disease, the presence of both normal and abnormal huntingtin expressed by the Huntington's disease gene. They found that the protein is in most neurons, that it is not particularly prominent in the types of neurons that die in Huntington's disease, and that it is associated with only certain parts of the cell, namely the microtubules and, to a lesser extent, synaptic vesicles.
Microtubules are important cytoskeletal structures in neurons that help give them shape and provide a scaffolding for proteins and organelles to be transported over or anchored to.
"...we speculate that the mutation impairs the cytoskeletal anchoring or transport of mitochondria, vesicles or other organelles or molecules," the authors reported.
"Thus, the pathophysiology of HD (Huntington's disease) likely depends on the effect of the mutant allele at the protein level. Understanding huntingtin is therefore crucial for determining how the genetic mutation could be linked to the pathophysiology of HD and for developing treatments based on the molecular defect."
The Emory discovery comes amidst a rush of similar reports by Huntington's disease researchers from Johns Hopkins, Massachusetts General Hospital and a research group in France, all validating the expression of huntingtin by the IT15 gene.
According to Hersch, the Emory team used monoclonal and polyclonal antibodies to track the protein. Use of an anatomic technique called immunogold allowed the Emory team to identify not only the presence of huntingtin, but to learn more about its function.
"Perhaps the HD mutation alters the anchoring or intracellular transport of mitochondria, RNA or metabolically relevant proteins," the authors reported. Such an alteration could provide a link between the genetic mutation and current ideas about neuronal death in HD.
The Emory team already is conducting further studies to better characterize huntingtin and how its expression by the IT15 gene leads to the clinical symptoms associated with Huntington's disease.
In addition to Hersch, who was senior author of the paper and is an assistant professor of neurology, other authors included Claire-Anne Gutekunst, (first author and postdoctoral student in Hersch's lab); Allan I. Levey, associate professor of neurology; Craig J. Heilman; William L. Whaley, assistant professor of psychiatry and behavioral sciences; Hong Yi; Norman R. Nash; Howard D. Rees, assistant professor of psychiatry and behavioral sciences; and John J. Madden, associate professor of psychiatry and behavioral sciences.
Huntington's disease is an inherited disorder characterized by jerky, involuntary movements called chorea, and progressive dementia -- all caused by the progressive loss of nerve cell clusters in the basal ganglia region of the brain. Symptoms usually do not become apparent until the third to fifth decades of life. Children of carriers of the Huntington's disease gene have a 50 percent chance of inheriting the gene. Genetic testing now is available to confirm the presence of the gene.
-- Lorri Preston