Biology subjects

Boros, B. D.

Publications and source records attributed to Boros, B. D..

3 recordsLinked to original sources

bioRxiv2026

Protein expression is amplified by stabilizing mRNA using gene-specific antisense oligonucleotides

Effective and safe strategies to restore gene expression in haploinsufficiency disorders or to augment protective protein signaling have long been attractive but challenging therapeutic goals. Here, we demonstrate the potential of antisense oligonucleotides (ASOs) to upregulate gene targets through mRNA stabilization. The 3 untranslated regions (UTRs) of mRNAs regulate stability via activating and repressive elements. One prominent destabilizing cis-element found in ~30% of transcripts is the Pumilio RNA-binding protein recognition element (PRE), which can be targeted to enable gene-specific protein upregulation. A scan for PREs highlights hundreds of disease-relevant transcripts that may be targetable via ASO-mediated gene-specific blocking of Pumilio binding. We show that masking specific PREs with ASOs produces sustained protein upregulation through mRNA stabilization using multiple reporter and endogenous gene targets. Using PRE-masking ASOs, we neutralized PRE-mediated destabilization of TANK-binding kinase-1 (TBK1) mRNA and restored TBK1 protein expression in participant-derived fibroblasts with TBK1 haploinsufficiency, causal for amyotrophic lateral sclerosis. Additionally, by targeting PRE sites in the myoprotective gene follistatin (FST), we achieved effective FST mRNA upregulation in tested mouse tissues. These findings suggest that ASO strategies that neutralize destabilizing 3UTR sequences like PREs may provide a powerful approach to upregulate haploinsufficiency-related genes or enhance protective protein levels for therapeutic benefit.

molecular biology↗

bioRxiv2025

Prior epigenetic status predicts future susceptibility to seizures in mice

Wide variation of responses to identical stimuli presented to genetically inbred mice suggests the hypothesis that stochastic epigenetic variation during neurodevelopment can mediate such phenotypic differences. However , this hypothesis is largely untested since capturing pre-existing molecular states requires non-destructive, longitudinal recording. Therefore, we tested the potential of Calling Cards (CC) to record transient neuronal enhancer activity during postnatal development, and thereby associate epigenetic variation with a subsequent phenotypic presentation - degree of seizure response to the pro-convulsant pentylenetetrazol. We show that recorded differences in epigenetics at 243 loci predict a severe vs. mild response, and that these are enriched near genes associated with human epilepsy. We also validated pharmacologically a seizure -modifying role for two novel genes, Htr1f and Let7c. This proof-of-principle supports using CC broadly to discover predisposition loci for other neuropsychiatric traits and behaviors. Finally, as, human disease is also influenced by non-inherited factors, similar epigenetic predispositions are possible in humans.

genomics↗

bioRxiv2018

Distinct and Complementary Functions of Rho kinase isoforms ROCK1 and ROCK2 in Prefrontal Cortex Structural Plasticity

Twenty-nine protein kinase inhibitors have been used to treat human diseases. Out of these, two are Rho-associated protein kinase (ROCK) 1 and 2 inhibitors. ROCKs are attractive drug targets for a range of neurologic disorders; however a critical barrier to ROCK-based therapeutics is ambiguity over whether there are isoform-specific roles for ROCKs in neuronal structural plasticity. Here, we used a genetics approach to address this long-standing question. Both male and female adult ROCK1+/- and ROCK2+/- mice exhibited anxiety-like behaviors compared to littermate controls. Individual pyramidal neurons in the medial prefrontal cortex (mPFC) were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and neuronal 3D reconstructions for morphometry analysis. Increased apical and basolateral dendritic length and intersections were observed in ROCK1+/- but not ROCK2+/- mice. Although dendritic spine densities were comparable among genotypes, apical spine extent was decreased in ROCK1+/- but increased in ROCK2+/- mice. Spine head and neck diameter were reduced similarly in ROCK1+/- and ROCK2+/- mice; however certain spine morphologic subclasses were more affected than others in a genotype-dependent manner. Biochemical analyses of ROCK substrates revealed that phosphorylation of LIM kinase was reduced in synaptic fractions from ROCK1+/- or ROCK2+/- mice, correlating to overlapping spine morphology phenotypes. Collectively, these observations implicate ROCK1 as a novel regulatory factor of neuronal dendritic structure and detail distinct and complementary roles of ROCKs in mPFC dendritic spine structural plasticity. This study provides a fundamental basis for current and future development of isoform-selective ROCK inhibitors to treat neurologic disorders.\n\nSignificance StatementThe Rho-associated protein kinases (ROCK) 1 and 2 heavily influence neuronal architecture and synaptic plasticity. ROCKs are exciting drug targets and pan-ROCK inhibitors are clinically approved to treat hypertension, heart failure, glaucoma, spinal cord injury, and stroke. However development of isoform-specific ROCK inhibitors is hampered due to ambiguity over ROCK1- or ROCK2-specific functions in the brain. Our study begins to address this critical barrier and demonstrates that ROCK1 can mediate the dendritic arbor of neurons while both ROCK1 and ROCK2 heavily influence dendritic spine morphology. This study highlights distinct and complementary roles for ROCK1 and ROCK1 in prefrontal cortex structural plasticity and provides a fundamental basis for future development of isoform-selective ROCK inhibitors to treat neurologic disorders.

neuroscience↗