Huntington’s researchers chase a new lead

RIKEN researchers have come up with a novel mechanism to explain the onset of Huntington’s disease. They have found that mice carrying the mutation that leads to the degenerative nerve condition also have lower levels of the transcription factor known as nuclear factor Y (NF-Y). This transcription factor regulates the production of heat shock proteins (HSPs) 70 and 40 which control the folding, unfolding and assembling of proteins critical to proper nerve cell function. The researchers believe their work could lead to new treatments for the disease which involve boosting NF-Y.

Huntington’s disease typically leads to abnormal body movements and affects behavior and mental abilities sometime after the age of 40 (Fig. 1). The direct cause—a mutation in the Huntingtin gene—has been known for about 15 years, but not how it leads to the observed degeneration of nerves in specific regions of the brain. What is known, however, is that protein made from the mutant gene forms aggregates in nerve cells and they subsequently degenerate. The aggregation process can be suppressed by heat shock proteins. Recent studies have shown that transcription factors are incorporated into the aggregates thus affecting the activity of the genes they control.

In a paper in The EMBO Journal ¹, the researchers from RIKEN’s Brain Science Institute in Wako detail their discovery that the transcription factor for HSP70 is among those caught up in the mutant Huntingtin aggregates. This leads to low levels of HSP70 which could not only affect the folding and assembly of a great many proteins, but could also decrease the suppression of aggregate formation.

The researchers initially discovered components of NF-Y in mutant Huntingtin aggregates using mass spectrometry. They then confirmed presence of the NF-Y components by tagging them. They subsequently found the same NF-Y components in aggregates in the brains of model mice with Huntington’s disease, and showed that this was associated with decreased activity of the genes for making the heat shock proteins. Their work has allowed them to put together a hypothetical model of the progression of Huntington’s disease.

“We now want to try to confirm our results using NF-Y knockout mice,” says Nobuyuki Nukina, who leads the team. “We predict the expression of genes will change in a similar way to Huntington’s disease.

“If so, NF-Y could become a target for treatment of the disease. It is very important to stop aggregation formation, and that could mean activating NF-Y.”