New Test Could Help Predict Onset, Course of Huntington’s, Lab Researchers Say

New Test Could Help Predict Onset, Course of Huntington’s, Lab Researchers Say
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mHTT seeding activity predict

Short huntingtin (HTT) protein fibers precede the formation of larger deposits that accumulate in the brains of those affected by Huntington’s disease, preclinical results reveal.

These findings one day may help researchers predict the onset and course of the disease.

The study, “mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington’s Disease,” was published in the journal Molecular Cell.

Researchers at the Max Delbrück Center for Molecular Medicine (MDC) developed a new method called FRASE assay, and revealed for the first time that mutated HTT (mHTT) seeding activity is detectable even before Huntington’s symptoms‘ onset.

The FRASE assay combines two engineered HTT-based small proteins that were modified, when close to each other, to release a fluorescent signal. Using this method makes it possible to effectively measure mHTT seeding activity; as the HTT protein accumulates it also will increase the amount of fluorescent signal that can be detected.

When researchers tested the assay on brain tissue samples collected from mice with Huntington’s disease they could effectively detect mHTT seeding activity by looking at a positive fluorescent signal.

Importantly, the method also could detect mHTT seeding activity in brain samples collected postmortem (after death) from patients with Huntington’s, but not in control samples from healthy individuals. This  indicated the method “is suitable to discriminate between patients and healthy individuals,” researchers wrote.

The FRASE assay could detect mHTT seeding activity in diseased mice long before the protein aggregates could be seen and motor symptoms were present. These very small protein precursors (about ten-thousandths of a millimeter long) consisted of mutated HTT proteins “glued” to one another.

“Our results are the best indication to date that seeding-competent huntingtin [HTT protein] fibers are actually responsible for the disorder,” Erich Wanker, PhD, professor at the MDC and senior author of the study, said in a press release.

“We believe this is the best evidence so far that the misfolded protein also triggers Huntington’s,” he said.

Using flies genetically engineered to develop Huntington’s disease, the team evaluated whether mHTT seeding activity could be used to predict disease course. mHTT seeding activity levels measured with the FRASE assay significantly correlated with increased mortality in these animals. In contrast, when using other alternative methods to quantify HTT aggregate formation, the team failed to find any association between mHTT seeding activity and shortening animals’ life span.

The researchers believe that mHTT seeding activity could be of “high value for monitoring disease onset and progression in patients with Huntington’s disease.” However, they said additional studies are warranted to determine if the FRASE assay can efficiently quantify mHTT seeding activity in biosamples whose collection is technically and ethically possible, such as cerebrospinal fluid, blood, or muscle tissue.

“It would be amazing if we could one day determine the disease progression,” Wanker said. Such information could not help not only monitor the disease, but also improve treatment regimens and support the development of more efficient therapies.

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