Strides in STXBP1: What Happened Last Month in STXBP1 Research?
So, what was new in May 2024?
As we move into summer, we generally see fewer research papers published and May, like April, was a slow month.
A paper from a research group in Japan took a closer look at an interesting finding that had been reported a few years back. Previous studies performed in isolated cells had suggested that STXBP1 acts as a chaperone protein to another presynaptic protein called alpha-synuclein (a-Syn). Abnormal aggregation, or ‘clumping’ of a-Syn has been linked to neurodegenerative disorders, like Parkinson’s disease, and the suggestion from the previous studies was that STXBP1 helps prevent this aggregation. Further, those previous studies found that certain mutations in STXBP1 resulted in loss of its chaperone function resulting in co-aggregation of the mutant STXBP1 and a-Syn. The Japanese group expanded this story by looking at flies that contain a human a-Syn gene. These flies, which are used as models of Parkinson’s disease, show signs of eye degeneration, motor impairments, and loss of dopamine neurons. The group found that if they mutated one copy of the fly Stxbp1 gene (called Rop) in the a-Syn flies then the eye degeneration, motor impairments, and dopamine neuron loss was much worse. They then treated these flies with a compound called trehalose, a chemical chaperone that was shown to have positive effects on mutant STXBP1 in the same paper that suggested that 4-phenylbutyrate (Ravicti) could be used to treat STXBP1-RD. The trehalose prevented the enhanced neurotoxic effects of the mutated Rop gene. This study supports the idea that some STXBP1 mutations could interact with a-Syn in such a way as to increase or cause neurodegeneration. As this study was performed in flies, much more work will need to be done to fully understand any potential relationship between STXBP1 and a-Syn in people.
The team at CHOP published a paper where they looked at clinical histories of 52,143 people with documented speech and language disorders using electronic medical records. They found a wide range of speech and language diagnoses within the cohort though the top 5 speech and language diagnoses accounted for about 80% of all cases. They also examined the association of speech and language diagnoses with other neurological diagnoses and with genetic conditions. They found significant overlap of speech and language diagnoses with diagnoses of developmental disorders, epilepsy, and to a lesser extent, movement disorders. They also found that 607 individuals had a genetic diagnosis, with STXBP1 being most common (a total of 21 individuals). Next, they looked at specific speech and language diagnoses in specific genetic conditions and found that STXBP1 was particularly associated with a diagnosis of aphasia (decreased ability to comprehend or formulate language) and that this relationship was stronger than any other genetic condition and speech/language diagnosis relationship.
Mature onset diabetes of the young, or MODY, refers to any of several rare hereditary forms of diabetes caused by mutations in autosomal dominant genes that disrupt insulin production. Researchers in China examined a patient with MODY caused by a mutation in the KCNJ11 gene, which makes a protein used to construct what is known as an ATP-sensitive potassium channel (K-ATP). The researchers found that if they expressed this mutant gene in pancreatic b-cells, which are the cells in the body that produce and excrete insulin, the amount of insulin excreted by the cells when exposed to glucose was significantly reduced and this was coupled with a decrease in STXBP1 expression. Insulin secretion from b-cells is an exocytosis process, like the release of neurotransmitters from neurons, and STXBP1’s role in insulin secretion is an example of one of its non-neuronal functions. Interestingly, mutations in STXBP1 have so far not been associated with diabetes.
