Skip to main content
Premium Trial:

Request an Annual Quote

New Research Gives Clues to the Mechanism of Mutant Huntingtin

Premium

Researchers at Ontario’s McMaster University have made use of live cell analysis technologies to get a glimpse, in real time, of how the huntingtin protein goes awry in Huntington’s disease. A large portion of their work was done in the new McMaster biophotonics facility, and future research, according to Ray Truant, will be done at their high-throughput screening lab.

Truant, an assistant professor in the department of biochemistry and biomedical sciences, has been studying the role of heat shock proteins in polyglutamine diseases like Huntington’s disease for almost a decade. While people know which gene is involved in causing this neuron-degenerating disease, the role of its mutant expressed protein, huntingtin, is still largely unknown.

“What people see in Huntington’s disease is that the [mutant] huntingtin protein appears to accumulate in the nucleus,” Truant says. “My lab’s expertise is … finding sequences within proteins that mediate targeting of those proteins within cells. In particular, we’re interested in what targets the protein into the nucleus and what targets it to come back out again.”

Previous work found a sequence signal in the carboxy terminus of huntingtin that mediated its export from the nucleus; Truant was interested in what mediated its import. Scientists in his team compared huntingtin to other species’ versions, and located a perfectly homologous 18-mer starting region that was completely conserved across species, allowing them to conclude that this must be a functionally important region. Using a fluorescent tag and live cell imaging, “what we could see was that the protein was being targeted to the endoplasmic reticulum,” Truant says. “The thing that we learned from live cell imaging that we would not have learned by any other method was that if we did anything to stress the cells, like increase the temperature or decrease the temperature all of the sudden, that targeting would disappear. This corresponded with huntingtin’s ability to then enter the nucleus.”

An important part of huntingtin’s activity in the stress response is leaving the nucleus after it has done its job, which Truant and others believe could involve a range of things, from turning on transcription to exporting other proteins into the cytoplasm. In observing the mutant form, they found that any slight conformational change “would greatly increase the toxicity because it was no longer targeting the ER and it was constitutively going into the nucleus,” Truant says. “So this says to us that we need to keep huntingtin targeted in the cytoplasm and prevent the mutant protein from entering the nucleus.”

Knowing that the 18-mer region is affected by phosphorylation, Truant will begin working out methods to target that region with kinase inhibitors in future experiments. Using high-content screening techniques and RNAi technologies, his group hopes to target small molecule therapeutics that are already on the shelf and could be tweaked to target mutant huntingtin. Kinase inhibitors form the largest number of successful new drugs that are being developed and marketed for a diversity of diseases, including stroke, arthritis, and cancer.

The Scan

Not Yet a Permanent One

NPR says the lack of a permanent Food and Drug Administration commissioner has "flummoxed" public health officials.

Unfair Targeting

Technology Review writes that a new report says the US has been unfairly targeting Chinese and Chinese-American individuals in economic espionage cases.

Limited Rapid Testing

The New York Times wonders why rapid tests for COVID-19 are not widely available in the US.

Genome Research Papers on IPAFinder, Structural Variant Expression Effects, Single-Cell RNA-Seq Markers

In Genome Research this week: IPAFinder method to detect intronic polyadenylation, influence of structural variants on gene expression, and more.