From Israel to Canada, cancer to Huntington’s
When Barak Rotblat moved to Canada to start research into childhood cancers, he had no idea that it would lead to insights into Huntington’s disease, one of the most debilitating forms of neurodegeneration. Here he tells us why he’s glad he went against his initial instincts.
As my PhD at Tel Aviv University, Israel, was coming to an end, I was looking around for a lab in which to continue my training. My PhD was in the field of cell signalling ― studying how components within cells interact ― and I knew I wanted to stay in that field.
An opportunity came up with a researcher called Poul Sorensen at the University of British Columbia in Vancouver, Canada. At first I was a bit reluctant. I was mainly interested in how proteins move around in cells, while Poul was a pathologist studying genes involved in childhood cancers. However, when I looked into the project a little closer, I realised that analysing the genes that go wrong in childhood cancers could lead to fundamental understanding of cellular processes that affect all cells.
A few months later I was getting on a plane to Canada.
A couple of years before I arrived, the Sorensen lab had discovered a gene called HACE1. They had found it by studying samples from a child with a kidney cancer called Wilms’ tumour. HACE1 helps cells to tolerate stresses such as chemicals which can build up in the cell and cause cancer. It is also highly active in the brain. When I arrived at the lab there were some questions to answer: what biological functions does HACE1 perform? What does it do in the brain?
A common stress in any biological organism is oxidative stress. Though we need oxygen to live, it can also form highly reactive molecular species which damage molecules such as proteins and DNA in a very similar chemical process to that which causes metal to rust. Oxidative stress happens in various ageing-related diseases such as cancer, neurodegeneration and diabetes, and for the past two decades there has been a surge of work trying to dissect what is happening in the cells that sense and respond to oxidative stress. These studies led to the identification of the NRF2 system. NRF2 is a protein that springs into action under oxidative stress, setting off a cascade of events that protect the cell.
Could it be that HACE1 was a part of this system? That would explain why not having it results in hypersensitivity to stress. It turned out I was right ― experiments performed by Roberto Nitsch, a friend and colleague at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences, confirmed my own findings in the brains of mice.
I wanted to know if HACE1 plays a role in neurodegenerative disease. A colleague introduced me to Dagmar Ehrnhoefer, a post doc at the Michael Hayden lab in the Centre for Molecular Medicine and Therapeutics in Vancouver, who studies Huntington’s disease. She was excited to hear HACE1 might be protective in this context as well.
Huntington’s disease is caused by a mutation in the Huntingtin gene, which creates a defective protein that disrupts normal cell functions. Cells manage to tolerate this mutant protein in the short term, but after three to five decades they start to die. People with Huntington’s have the mutant protein in every cell in their body, but neurons are especially vulnerable to it ― particularly neurons in an area of the brain called the striatum. As the disease progresses, patients gradually lose brain functions, become paralysed and die. There is a genetic test for the disease, but no treatment.
Dagmar and I looked at the levels of HACE1 in different regions in the brains of people with Huntington’s disease and found that HACE1 levels were very low in the striatum. We hypothesised that losing HACE1, which helps cells tolerate oxidative stress, might make striatal cells more vulnerable to the mutant Huntingtin protein. We tested this theory using cells in culture, and found that restoring HACE1 function in diseased cells restored their ability to tolerate the oxidative stress that is associated with the mutant Huntingtin protein.
While the project was evolving I received an invitation from Gerry Melino at the MRC Toxicology Unit in Leicester, and I took him up on it, partly because I wanted to move to Europe with my wife and new son to be closer to our family in Israel. Gerry is a long-time friend of Poul’s, and was very enthusiastic when he found out that I wished to complete the project at the MRC. By a stroke of luck, his lab was studying genes that are involved in cancer and in brain development.
When I look back at the journey I made with this project I realise how unlikely it is that I would start to work on a gene discovered in childhood cancer and end up finding a new cellular process that is important in neurodegeneration. Dagmar and her colleagues are now investigating how HACE1 protects mice with Huntington’s disease from neurodegeneration in the hope that this will lead to new treatments.