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

Welcome back. After a summer of no STXBP1 publications, September brings with it cooler temperatures (for some) and some new research.

So, what was new in September?

Hypoxia is a condition where tissues in the body are starved of oxygen. If this occurs in neonates they can develop neonatal encephalopathy (NE), a neurological syndrome characterized by low levels of consciousness, abnormalities in muscle tone, seizures, and depressed breathing. Hypoxia-induced NE can be caused by reduced oxygen or blood flow at birth but approximately 50% of cases do not appear to be caused by this. A research group in Korea was interested to see if there might be any genetic causes for hypoxia-induced NE. They looked at 34 newborns diagnosed with hypoxia-induced NE who had undergone genetic testing. They found that 11 of the newborns had pathogenic genetic variants associated with a variety of developmental epileptic encephalopathies, including one with a mutation in STXBP1. The team concluded that genetic testing should be performed on newborns with hypoxia-induced NE as one way of trying to identify a cause.

Researcher and STXBP1 dad, Ben Prosser, his lab, and colleagues at UPenn reported on their generation of a humanized Stxbp1 mouse. There are several gene therapy approaches that directly target a specific gene or RNA, including the use of antisense oligonucleotides (ASOs), and direct gene editing via CRISPR-Cas (for a review of gene therapy approaches watch my recent video; Gene Therapy Approaches for STXBP1 Related Disorders (youtube.com)). Since the mouse Stxbp1 gene and human STXBP1 gene are not identical, it can be difficult or impossible to test some of these gene therapy approaches in mice. Dr. Prosser and is group replaced the mouse Stxbp1 gene with the human gene, generating a line of Stxbp1 humanized mice. They were able to generate hybrid mice that had one human copy and one mouse copy of the gene (Stxbp1Hu/+) and fully humanized mice that had two copies of the human gene (Stxbp1Hu/Hu). They found that the fully humanized mice, Stxbp1Hu/Hu, had significantly reduced viability, about 90% of males died by 9 weeks of age whereas about 30% of females died by 36 weeks of age. They also found that the Stxbp1Hu/Hu had about a 40% less STXBP1 protein than expected. It’s unclear at this time why the humanized Stxbp1 mice have these issues (the group has also generated humanized Syngap1 mice, which do not demonstrate similar problems); however, they are now being used to help in developing targeted gene therapies.

Regulated cell death (RCD) is a well-organized process in various cells that leads to cell death. There are 12 different types of RCD known to be associated with various cancers. A group in China examined these 12 RCDs in breast cancer by examining varying patterns of gene expression changes. They found that the expression pattern of 6 different genes, one of which was STXBP1, could be used to calculate a novel RCD score to predict the prognosis of patients with the most common type of breast cancer (HR+/HER2- breast cancer). STXBP1 is a regulator of lysosome-dependent cell death (a type of RCD) and increased expression was associated with poorer overall survival.

Alzheimer’s disease (AD) is a highly prevalent, progressive neurodegenerative disorder Despite huge expenditures in research and drug development, AD has proven difficult to treat (over 99% of investigation drug candidates fail). One hypothesis for this difficulty suggests that AD should not be thought of as a single disorder but as a network of ‘endophenotypes’, that is multiple different pathologies (e.g. neuroinflammation, mitochondrial dysfunction, vascular changes, etc...). Network medicine is a way to explore the molecular relationships (proteins, RNAs, metabolites) between these endophenotypes to identify new drug targets or biomarkers. A research team in China used such an approach to examine protein and RNA differences in AD patients and in AD mouse models to uncover novel AD biomarkers that could be used to evaluate repurposed drugs and found 3, including STXBP1.