Using genetically modified zebrafish, UCL scientists have identified a novel gene affected in a devastating disorder with childhood-onset Parkinsonism. Indeed, when a drug that worked in the fish was given to one of the children, she regained the ability to walk.
The researchers studied a group of nine children who suffered from severely disabling neurological symptoms including difficulties in walking and talking. Dr Karin Tuschl and her team at the UCL Great Ormond Street Institute of Child Health and UCL Department of Cell and Developmental Biology used state of the art genome editing in zebrafish to validate the identity of the gene affected in these children.
The scientists disrupted a gene known as slc39a14 in the fish, which is important for transporting metals in the body. Disrupting the transporter in fish led to a build up of manganese in the brain and impaired motor behaviour. As similar symptoms were seen in the patients, this confirmed that slc39A14 is required to clear manganese from the body and protect it from manganese toxicity. It also confirmed that the scientists had found the gene causing the disease in the patients.
Dr Karin Tuschl explains: "Our findings provide families with a genetic diagnosis for their children's condition, thereby facilitating counselling for future pregnancies."
The research is also promising in terms of potential treatment. By identifying manganese as the crucial factor, the researchers have been able to show that a drug called disodium calcium edetate is capable of lowering blood manganese levels in zebrafish. Treatment of a child with the same drug who was severely affected by this disorder and could not walk led to a dramatic improvement of her clinical symptoms so that she regained her ability to walk.
Dr Tuschl adds: "The research not only facilitates correct diagnosis of patients with this disease, but may also provide an avenue for effective treatment. By studying human patients with a rare metabolic defect, the study has helped to address the fundamental issue of how manganese metabolism is regulated in vertebrates. This is particularly topical, given increasing scientific interest into the role of manganese dysregulation in more common neurodegenerative conditions like Parkinson's disease."