University of Delaware assistant professor David W. Colby
is coauthor of a paper in Journal
of Biological Chemistry that suggests protein misfolding may occur early in the
pathogenesis, or development, of Huntington’s disease.
Huntington’s disease (HD) is one of several neurological
diseases, such as Alzheimer’s disease or prion disease, associated with
proteins that fold into abnormal structures. HD is characterized by progressive
motor impairment, cognitive decline and behavioral abnormalities, and
ultimately death.
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.
