The Mechanisms of a Rare Neurological Disorder
Researchers from the University of Liverpool have identified how mutations in a gene coding for hippocalcin can cause dystonia, a rare neurological movement disorder. The study, published in Human Molecular Genetics, was able to demonstrate for the first time how T71N and A190T mutations in the gene distorted the action of hippocalcin to over-activate neurons and cause the disease.
Dystonia can be the result of an injury or can be inherited and develop progressively from childhood, characterised by uncontrollable muscle contractions that result in repetitive movements and painful posture. It is estimated that around 70,000 people in the UK are currently affected by the condition and while it can be effectively managed with treatment, there is no cure.
Hippocalcin is a member of a family of proteins that are involved in signalling within the nervous system. Previous work has shown that mutations within hippocalcin are linked to the condition, but the mechanism behind this link hasn’t been clearly understood. This new study, completed by researchers at the University’s Institute of Translational Medicine (ITM) and Institute of Integrative Biology (IIB), focused on identifying the mutations responsible for causing the disease and demonstrating the mechanism of action.
The study demonstrated that the T71N and A190T mutations didn’t result in changes in gene expression or in protein structure, but did cause subtle defects in how hippocalcin controls neuron activation. Hippocalcin can interact with specific types of calcium channels of synapses, through which it can instigate signal activation. The team found that when the hippocalcin was mutated, the protein would overstimulate the channels, forcing the neuron to fire erroneously.
“We can now understand for the first time how these mutations would have important physiological consequences that would lead to abnormalities in neuronal function,” said Nordine Helassa, Ph.D., first author of the paper, “Excessive neuronal activation that could result in aberrant signalling in the brain of affected individuals.”
This work is still very young and more study is needed to utilise the discoveries of this investigation. However, understanding how hippocalcin can result in dystonia may provide a new approach for drug developers to treat the condition.
“These findings provide a clue towards the development of a potential new treatment as it is possible that use of drugs that inhibit the key calcium channels regulated by hippocalcin could help reduce the impact of the inherited disorder,” said Professor Bob Burgoyne, lead researcher, who has studied the hippocalcin family at ITM for the last 20 years.