May occur early in the development of Huntington’s disease
April 9, 2012 — University of Delaware assistant professor David W. Colby is coauthor of a paper in The Journal of Biological Chemistry that suggests protein misfolding may occur early in the pathogenesis, or development, of Huntington’s disease.
Protein Misfolding Detected Early in Pathogenesis of Transgenic Mouse Model of Huntington Disease Using Amyloid Seeding Assay
Background: Huntington disease is associated with protein misfolding.
Results: We developed an amyloid seeding assay for detecting misfolded huntingtin (HTT) protein and found early protein misfolding in a transgenic mouse model.
Conclusion: The amyloid seeding assay allows for sensitive detection of misfolded HTT.
Significance: The detection of misfolded HTT in young YAC128 mice suggests that protein misfolding may be an early event in pathogenesis.
The researchers developed a novel technology, called an amyloid seeding assay (ASA), to detect the misfolded protein, huntingtin, in laboratory mice at 11 weeks of age, more sensitively than traditional histology methods which don’t reveal large inclusions until much later in the pathogenic process, about 78 weeks.
According to Colby, the ASA takes advantage of the biophysical tendency of isolated misfolded huntingtin to act as a “seed” for the conversion of a monomeric polyglutamine peptide to a misfolded form, known as an amyloid fiber.
This results in the formation of additional amyloid protein, essentially amplifying the amount of misfolded protein in the sample. The amyloid can then be detected with the dye Thioflavin T and measured by a fluorescent detector.
“Alzheimer’s disease and prion disease brain tissue subjected to the same purification procedure did not do so, demonstrating the specificity of the ASA,” the paper states.
“Testing of experimental therapies is slow and expensive, given the time it takes for a misfolded protein to appear in a form detectable by traditional methods. We believe that the ASA can speed up this initial testing process and push promising therapies to clinical trial faster,” Colby said.
Press release courtesy of the University of Delaware. You can find the original press release here.
Photo courtesy of Wikipedia.