Scientists Discover the Way Huntington’s-related Protein Errors Occur

Enhancing a cell’s quality control mechanism to get rid of the faulty proteins that are a hallmark of Huntington’s disease may help prevent patients’ motor and cognitive loss, a study suggests.

The researchers’ discovery of how the quality control mechanism fails may pave the way toward the development of novel therapies aimed at clearing neurons of the accumulated faulty proteins that are present in other neurodegenerative conditions as well.

The research, “Abnormal Degradation Of The Neuronal Stress-Protective Transcription Factor HSF1 In Huntington’s Disease,” was published in the journal Nature Communications

Several neurological diseases, such as Huntington’s, Alzheimer’s and Parkinson’s, are caused by the progressive accumulation of misfolded proteins. The proteins were not produced correctly so they don’t work properly. By impairing neuron activity, they lead to neuron loss, cognitive decline and inability to control movement.

Healthy cells have a mechanism that eliminates faulty proteins, but in Huntington’s, the mechanism does not work properly.

“Normally when proteins misfold, the cells have a mechanism to cope,” Dennis Thiele, PhD, the study’s senior author, said in a news release. “These quality control mechanisms can prod the proteins back into their normal three-dimensional shape, or if the damage is too extensive, target them for removal in the cellular garbage disposal. In Huntington’s disease, that’s not happening.”

The quality control mechanism is dependent on proteins called chaperones. They ensure that each protein produced is folded correctly, meaning its configuration is correct.

In Huntington’s disease, chaperones are present in abnormally low levels. The reason for this was unknown until now.

Using a series of laboratory experiments with mouse and human cells, researchers found that a protein called HSF1, which controls chaperone production, is destroyed in Huntington’s disease. This happens because mutant huntingtin — the faulty protein that leads to the disease — increases the expression of another protein, CK2, which modifies HSF1, sending it to degradation.

Without HSF1, a lot fewer chaperones are produced. This leads to faulty proteins accumulating in neurons, promoting Huntington’s.

“We have identified a potential new target for a drug intervention in Huntington’s disease,” Thiele said, “but there are a lot of basic questions that still need to be answered.”