Strides in STXBP1: What Happened Last Month in STXBP1 Research?

So, what’s new in November 2024?

Zach Grinspan and the teams at Weill Cornell Medicine, Vanderbilt University Medical Center, and Children’s Hospital Colorado released their findings on the use of 4-Phenylbutyrate to treat STXBP1 and SLC6A1. This study was intended to test if the drug 4-Phenylbutyrate (4-PB), which has been approved by the FDA to treat urea cycle disorders, could be repurposed to treat seizures in children with STXBP1 or SLC6A1 disorders. Twenty children (10 each) were enrolled in the study and treated with 4-PB for up to 3 years. During the trial, 4-PB was well tolerated as a medication, with few adverse side effects. Of the 10 STXers, following 10 weeks of treatment, 6 had a positive clinical response in that their seizure burden significantly improved, 2 had an intermediate response (transient decrease in seizures, reduced need for rescue medication), and 2 had no response to the drug. Of note, the two non-responders and 1 intermediate responder suffered from epileptic spasms whereas none of the positive responders had epileptic spasms. Nine of the 10 children continued 4-PB treatment for 1-2 years. Results over this time were somewhat mixed with some children seeing an increase in seizure clusters while a couple of children saw their seizures resolve. During the course of the study most children also demonstrated positive changes on their EEGs. Overall, the results are encouraging and demonstrate that repurposed drugs can be use to treat symptoms, such as seizure burden, in children with STXBP1-RD.

A paper from Chinese researchers identified the STXBP1 gene as one of nine ‘hub genes’ associated with copper metabolism defects in Parkison’s disease (PD). Copper is essential for some proteins and enzymes to function correctly. Too little or too much copper in the brain can lead to neurotoxicity, impaired mitochondrial function, and pathogenic protein aggregation. There is evidence that people who have PD have altered levels of copper in the brain and CSF, the researchers were interested in identifying genes that may play a role in this impaired copper metabolism. They compared genes that were differentially expressed in people with PD compared to controls, to genes known to be associated with copper metabolism, and genes associated with neuroinflammation (which is also found in PD) and found 9 ‘hub genes’, one of which is STXBP1. They then examined the CSF of PD patients and found that STXBP1 RNA was significantly decreased compared to control CSF. Interestingly, other researchers have previously suggested that the STXBP1 protein may act as a chaperone protein to a protein called alpha-synuclein. Aggregation of alpha-synuclein protein is a well-known hallmark, and a suggested cause of the neuropathology associated with PD. A decrease in STXBP1 protein expression in PD could lead to less protein available to chaperone alpha-synuclein thus allowing alpha-synuclein to self-aggregate.