The gene, UNC13A, is associated with a novel syndrome, that is linked to ALS and dementia. Dr Reza Asadollahi, a senior lecturer in genetics at the University of Greenwich, and colleagues have discovered that when UNC13A mutates, it is responsible for multifaceted neurodevelopmental/neurodegenerative diseases, with a crucial link to ALS and dementia. The findings were published in Nature Genetics.
UNC13A is the gene responsible for producing a synaptic protein that is key in synaptic transmission, or communication between neurons. Dr Asadollahi first saw a variant of the gene in a patient and then contacted fellow academics around the world to ask if it was present in other patients.
He and his colleagues from Germany and USA then undertook detailed study of neurons in mice and the C. elegans worm (commonly known as a roundworm) which also have the gene and are good models for movement and neuron communication. They discovered that whilst symptoms of the novel syndrome, called UNC13A Syndrome, are not consistent because it depends on where the mutation is on the gene, there are three main expressions of the disease.
The first is under-expression, where the gene is not expressed fully, instead it is less than 50% expressed. In this case, there are two mutations on the gene – one from each parent - and this results in profound developmental delay and a respiratory problem where muscles become weak. Depending on the severity, this can lead to death.
The second expression occurs when just one amino acid is different, and this causes an overactivity of the protein which results in tremors, movement abnormalities and seizures which are resistant to therapy in the patients.
The final expression is familial (it runs through families) and causes mild learning difficulties and seizures, but it can be managed using medication.
Now Dr Asadollahi and his team are looking at treatments. He said:
“We are excited for the major step forward in understanding the critical role of the synaptic protein UNC13A in neurological disorders.
“Our new findings reveal that restoring UNC13A protein levels to just 50% may be sufficient to improve disease symptoms — and even 20–30% restoration appears to offer meaningful benefit.
“These results open a promising path toward new treatments for UNC13A syndrome, which will pave the way for ALS/dementia in the next steps, and our next phase of work will focus on developing targeted therapies guided by the precise disease mechanisms we have uncovered.”
