Biology subjects

Bengtson, M. H.

Publications and source records attributed to Bengtson, M. H..

2 recordsLinked to original sources

bioRxiv2025

Abnormal expression of splicing regulators RBFOX and NOVA is associated with aberrant splicing patterns at the Neurexin-3 gene in a monogenic autism spectrum disorder

Autism spectrum disorders are diseases characterized by a combination of cognitive, behavioral and neurological symptoms. A complex interplay between environmental factors and a multitude of genetic determinants, most of them composed of low-risk variants, impose difficulties in understanding the molecular and cellular underpinnings of these conditions. In some cases, autistic patients have been shown to display alterations in splicing patterns of several genes, but the extent to which this phenomenon is common in the context of these multifactorial disorders is unknown, nor is it known if monogenic cases of autism also display dysregulation of splicing. Moreover, very few studies have investigated the causal links between splicing alterations in specific genes and the phenotypic characteristics of the neural tissue in autism patients. In this study, we have focused on a monogenic type of autism caused by haploinsufficiency of the Transcription Factor 4 gene, known as Pitt-Hopkins Syndrome. We show that neurons and organoids derived from patients with this disease have altered expression of splicing regulators in the NOVA and RBFOX families, accompanied by aberrant splicing patterns in a substantial number of genes involved in neural tissue development and synapse organization. We focused on a gene encoding a member of the Neurexin Family, the splicing of which normally leads to the production of transcript variants coding for both transmembrane and secreted protein isoforms. In Pitt-Hopkins Syndrome neurons, we detected an aberrant splicing pattern that results in lower expression of the secreted isoform and its corresponding transcript, a phenomenon that may explain why the neural tissue in these patients have decreased electrical activity through impaired synapse organization. Our data shed light on the role splicing regulation plays in a monogenic type of autism.

neuroscience↗

bioRxiv2023

An experimental target-based platform in yeast for screening Plasmodium vivax deoxyhypusine synthase inhibitors

The enzyme deoxyhypusine synthase (DHS) catalyzes the first step in the post-translational modification of the eukaryotic translation factor 5A (eIF5A). This is the only protein known to contain the amino acid hypusine, which results from this modification. Both eIF5A and DHS are essential for cell viability in eukaryotes, and inhibiting DHS can be a promising strategy for the development of new therapeutic alternatives. The human and parasitic orthologous proteins are different enough to render selective targeting against infectious diseases; however, no DHS inhibitor selective for the parasite ortholog has previously been reported. Here, we established a yeast surrogate genetics platform to identify inhibitors of DHS from Plasmodium vivax, one of the major causative agents of malaria. We constructed genetically modified Saccharomyces cerevisiae strains expressing DHS genes from Homo sapiens (HsDHS) or P. vivax (PvDHS) in place of the endogenous DHS gene from S. cerevisiae. This new strain background was [~]60-fold more sensitive to an inhibitor of human DHS than the one previously used. Initially, a virtual screen using datasets from the ChEMBL-NTD database was performed. Candidate ligands were tested in growth assays using the newly generated yeast strains expressing heterologous DHS genes. Among these, two showed promise by preferentially reducing the growth of the PvDHS-expressing strain. Further, in a robotized assay, we screened 400 compounds from the Pathogen Box library using the same S. cerevisiae strains, and one compound preferentially reduced the growth of the PvDHS-expressing yeast strain. Western blot revealed that these compounds significantly reduced eIF5A hypusination in yeast. Our study demonstrates that this yeast-based platform is suitable for identifying and verifying candidate small molecule DHS inhibitors, selective for the parasite over the human ortholog.

synthetic biology↗