Scientists identify new Huntington disease pathway

February 19, 2014

(Medical Xpress)—An international group of researchers has identified a major new pathway thought to be involved in the development of Huntington disease. The findings, published in the Proceedings of the National Academy of Sciences journal, could eventually lead to new treatments for the disease, which currently has no cure.

Scientists at the BC Cancer Agency Research Centre and the Centre for Molecular Medicine and Therapeutics in Vancouver, Canada, and the MRC Toxicology Unit in Leicester, UK, studied mice and human tissue and found that the HACE1 gene is essential for mopping up toxic molecules during periods of oxidative stress, where harmful 'reactive oxygen species' build up in the cell.

Oxidative stress is thought to be involved in the development of a number of diseases including cancer and neurodegenerative disorders like Alzheimer's and Parkinson's disease. Therefore finding out how this process occurs in the body is important for understanding the course of disease.

The body has evolved highly effective defence mechanisms that sense and respond to oxidative stress to protect the cells from damage. One of these protective mechanisms is controlled by a molecule called NRF2 which springs into action and switches on the production of proteins and enzymes that detoxify the cell.

In this study, scientists found that the HACE1 also plays a vital role in this detoxification process, by activating NRF2. The authors believe that this mechanism goes wrong in Huntington's disease, leading to gradual destruction of nerve cells in the brain.

Lead author Dr Barak Rotblat, of the MRC Toxicology Unit, said:

"One of the early observations was that enhanced HACE1 expression rescued cells from mutant Huntingtin (the mutant protein that is responsible for Huntington disease) toxicity. We knew then that we had to figure out how HACE1 can protect these cells.

"Our evidence points towards a previously unknown role of HACE1 in Huntington disease and possibly other forms of neurodegeneration. It's very early days, but if we were able to find a way to boost this pathway, we might be able to develop a treatment that halts, or even reverses progression of Huntington disease."

HACE1 is already known to play a protective role against tumour formation, but its role in neurodegeneration has not been investigated before.

Dr Poul Sorensen, the senior author of the work from the BC Cancer Agency Research Centre and a Professor at the University of British Columbia, said:

"This is a glowing example of how work in one field, namely childhood cancers, where we first identified the HACE1 gene, has applications to a completely different disease, Huntington disease".

In this study, researchers looked at mice with and without the HACE1 gene and found that those without the gene had more oxidative stress in the brain, and their response to this was impaired. Depleting HACE1 in cells also resulted in reduced NRF2 activity, leading to lower tolerance against oxidative triggers.

The scientists also looked at human brain samples from Huntington disease patients and found a striking reduction of HACE1 levels in the striatum – the area of the brain where the disease develops and is most damaged.

Finally, they looked at HACE1 in a cellular model of Huntington disease. They found that upping expression of the gene in nerve precursor cells protected them against .

Explore further: New gene variants raise risk of neuroblastoma, influence tumor progression

More information: Barak Rotblat, Amber L. Southwell, Dagmar E. Ehrnhoefer, Niels H. Skotte, Martina Metzler, Sonia Franciosi, Gabriel Leprivier, Syam Prakash Somasekharan, Adi Barokas, Yu Deng, Tiffany Tang, Joan Mathers, Naniye Cetinbas, Mads Daugaard, Brian Kwok, Liheng Li, Christopher J. Carnie, Dieter Fink, Roberto Nitsch, Jason D. Galpin, Christopher A. Ahern, Gerry Melino, Josef M. Penninger, Michael R. Hayden, and Poul H. Sorensen. "HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response." PNAS 2014 ; published ahead of print February 10, 2014, DOI: 10.1073/pnas.1314421111

Related Stories

New gene variants increase risk of paediatric cancer

October 4, 2012

Two new gene variants have been discovered by researchers from Italy and the United States that increase the risk of neuroblastoma, a paediatric cancer. This discovery was made using automated technology to perform genome-wide ...

Breakthrough on Huntington's disease

May 23, 2013

Researchers at Lund University have succeeded in preventing very early symptoms of Huntington's disease, depression and anxiety, by deactivating the mutated huntingtin protein in the brains of mice.

Recommended for you

New insights on how cocaine changes the brain

November 25, 2015

The burst of energy and hyperactivity that comes with a cocaine high is a rather accurate reflection of what's going on in the brain of its users, finds a study published November 25 in Cell Reports. Through experiments conducted ...

Can physical exercise enhance long-term memory?

November 25, 2015

Exercise can enhance the development of new brain cells in the adult brain, a process called adult neurogenesis. These newborn brain cells play an important role in learning and memory. A new study has determined that mice ...

Umbilical cells help eye's neurons connect

November 24, 2015

Cells isolated from human umbilical cord tissue have been shown to produce molecules that help retinal neurons from the eyes of rats grow, connect and survive, according to Duke University researchers working with Janssen ...

Brain connections predict how well you can pay attention

November 24, 2015

During a 1959 television appearance, Jack Kerouac was asked how long it took him to write his novel On The Road. His response – three weeks – amazed the interviewer and ignited an enduring myth that the book was composed ...

No cable spaghetti in the brain

November 24, 2015

Our brain is a mysterious machine. Billions of nerve cells are connected such that they store information as efficiently as books are stored in a well-organized library. To this date, many details remain unclear, for instance ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.