Abnormal degradation of HSF1 may cause misfolded proteins in Huntington’s disease

Written by Hannah Makin

A recent study published in Nature Communications has shed new light onto the mechanisms behind the protein misfolding that leads to neuronal cell death in patients diagnosed with Huntington’s disease (HD).
To investigate the exact mechanisms behind these failures in quality control, researchers at the Duke University Medical Center (NC, USA) looked more closely into the role of chaperone proteins.

Senior author Dennis Thiele (Duke University) explained the importance of these chaperone proteins: “Normally when proteins misfold, the cells have a mechanism to cope. 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.”

In this study, researchers utilized chemical biology screening, yeast genetics, biochemistry, mouse models and stem cells from patients with HD to identify the mechanisms underlying protein misfolding and the importance of chaperone proteins in the development of HD.

Results demonstrated that an abnormal increase in the chemical modifier CK2 causes a subsequent increase in the degradation of the chaperone HSF1, which normally prevents the biochemical and neurobiological defects caused by protein misfolding.

Errant increases in this chaperone’s degradation may therefore lead to the protein misfolding observed in those with neurodegenerative diseases such as HD. By preventing this initial increase in CK2, scientists suggest that subsequent deficits in quality control could be avoided.

Thiele commented on his research group’s findings: “We demonstrated that we could restore the abundance of the protein chaperones by chemically inhibiting CK2 in a cell model of Huntington’s disease, or genetically lowering CK2 kinase levels in a Huntington’s disease mouse model. In both cases, we dramatically increased the number of healthy neurons and we prevented the muscle wasting that is commonly observed in Huntington’s disease.”

The next step will be to investigate these findings in further preclinical studies, but these results may offer a possible therapeutic target for HD, as well as many other similar conditions such as Parkinson’s and Alzheimer’s diseases.

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

Sources: Gomez-Pastor R, Burchfiel ET, Neef DW et al. Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease. Nat. Commun. doi:10.1038/ncomms14405 (2017) (Epub ahead of print); https://corporate.dukehealth.org/news-listing/cellular-quality-control-process-could-be-huntington%E2%80%99s-disease-drug-target