Scientists in Cambridge and Berlin – including biochemist Professor Florian Heyd – have made an important step in understanding and treating neurodegeneration by using a form of gene therapy to increase levels of cold shock protein in the brains of mice, protecting them against the potentially devastating impact of prion disease, which can cause rare forms of dementia. The discovery is a step towards harnessing the protective effects of cooling the brain to treat patients with acute brain injury and even to prevent different types of dementia, such as Alzheimer’s disease. The findings were published in the scientific journal EMBO Molecular Medicine.

When the body cools down significantly, it increases its levels of RBM3, a molecule known as the cold shock protein – a phenomenon first observed in hibernating animals. It is thought that during hibernation, the protein helps protect the brain from damage and allows it to continue to form new connections. Patients in intensive care units are sometimes treated using induced hypothermia, with the patients placed into a coma and their brains cooled to protect against damage. However, this comes with associated risks, such as blood clotting and pneumonia.

In 2015, Professor Giovanna Mallucci and colleagues at the University of Cambridge used studies on mice to show that RBM3 can protect the brain against damage associated with build-up of misfolded proteins. This kind of damage can lead to various forms of dementia, such as Alzheimer’s and Parkinson’s disease, and prion diseases such as Creutzfeldt-Jakob Disease (CJD). Building on this research, scientists at the UK Dementia Research Institute, University of Cambridge, and the Institute of Chemistry and Biochemistry, Freie Universität Berlin, wanted to find out whether the cold shock protein could be harnessed to treat patients without having to cool the body, as this would offer a safer treatment for acute brain injury or a potential way of protecting the brain against dementia. In their latest study, they investigated whether a form of gene therapy known as antisense oligonucleotides (ASOs) could increase levels of the cold shock protein in the brains of mice and protect them. The team examined the gene that codes for production of the cold shock protein and found that it contains a key element which, if removed or “dialed down” using an ASO, results in a long-lasting boost to production of RBM3.

“Essentially, the cold shock protein enables the brain to protect itself – in this case, against the damage nerve cells in the brain during prion disease,” says Mallucci. “Remarkably, we showed that just a single injection with the ASO was sufficient to provide long-lasting protection for these mice, preventing the inevitable progression of neurodegeneration.” If the findings can be replicated in humans, this approach could have major implications for the treatment of patients with a range of conditions who would otherwise be treated by therapeutic hypothermia. Professor Heyd from Freie Universität Berlin adds: “In particular, this approach offers the prospect of being able to protect against diseases such as Alzheimer’s and Parkinson’s disease, for which we have no reliable preventative treatments. We are still a long way off this stage as our work was only on mice, but if we can safely use ASOs to boost production of the cold shock protein in humans, it might be possible to prevent dementia.”

The research was supported by funding from Freie Universität Berlin, the German Research Foundation, and the UK Dementia Research Institute, which is in turn funded by the Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK.

This press release was originally issued by the University of Cambridge and adapted for distribution through Freie Universität Berlin.

Link to Study:

https://www.embopress.org/doi/full/10.15252/emmm.202217157

For further information and to request an interview, please contact:

Prof. Dr. Florian Heyd, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Tel.: +49 (0) 30 838 62938, Email: florian.heyd@fu-berlin.de