Biology subjects

Thorsell, A.

Publications and source records attributed to Thorsell, A..

4 recordsLinked to original sources

bioRxiv2025

Extended nuclear glycosylation is a common post-translational modification

In eukaryotes, glycans modify proteins in the secretory pathway and the extracellular space. Aside from nucleocytoplasmic O-GlcNAc, glycosylation is not considered a relevant post-translational modification in other cellular compartments. Here, we challenge this long-standing paradigm by showing that extended O-glycans are commonly found on intranuclear proteins. Through comprehensive genetic and biochemical analyses, we conclusively demonstrate that these O-glycans stem from the secretory pathway, yet are found on nuclear proteins across mammalian cell lines and primary cells. Using knock-out cell lines, we show mechanistically that nuclear glycans are shuttled to the nucleus via active vesicular transport. We identify several of these intranuclear glycoproteins as RNA-binding proteins, including KHSRP/FUBP2, RBM12, and RPP30. Lastly, we show that site-specific glycosylation of RPP30 is crucial for effective tRNA processing. Overall, our findings suggest a much broader role for glycosylation in regulating cellular functions and open up investigation into the role of glycans in more biological processes.

molecular biology↗

bioRxiv2025

Tirzepatide attenuates dopamine reward signaling and suppresses alcohol drinking and relapse-like behaviors in rodents

Alcohol use disorder (AUD) remains a major public health problem, with few effective medications currently available. However, peptides of the gut-brain axis appear to offer promising therapeutic targets for AUD as they influence the mesolimbic reward circuitry. Here, we examined the effects of tirzepatide, a long-acting dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist approved for diabetes and obesity, using behavioral assays, alcohol intake paradigms, and molecular analyses in rodents. First, tirzepatide effectively attenuated the rewarding properties of alcohol, measured through locomotor stimulation, conditioned place preference, and accumbal dopamine release. Subsequently, this GLP-1R/GIPR agonist dose-dependently reduced voluntary alcohol consumption, prevented binge and relapse-like drinking, and maintained efficacy during repeated administration. Finally, tirzepatide induced sustained synaptic depression in the lateral septum and further altered histone regulatory proteins in this region, suggesting a potential neural substrate for its effects. Moreover, the GLP-1R/GIPR agonist affected metabolic parameters including body weight, adipose tissue mass, hepatic triglycerides and circulating pro-inflammatory cytokines. Together, our findings suggest tirzepatide modulates alcohol-related behaviors through reward-related mechanisms while also affecting physiological consequences associated with long-term alcohol use. Given tirzepatides established clinical use and the consistency of effects observed here, these results support further investigation for treating AUD and associated complications. SIGNIFICANCE STATEMENTExisting treatments for alcohol use disorder show limited effectiveness, leaving patients without viable therapeutic options. We demonstrate that tirzepatide, a long-acting gut peptide-based drug already approved for diabetes and obesity, substantially reduces alcohol consumption and prevents relapse-like behavior across multiple preclinical models. Tirzepatide appears to work by influencing brain reward systems while simultaneously affecting metabolic complications common in alcohol disorders. Given tirzepatides clinical availability, these findings suggest repurposing a recently approved drug to tackle one of medicines more persistent treatment challenges.

neuroscience↗

bioRxiv2022

An equine Endothelin 3 cis-regulatory variant links blood pressure modulation to elite racing performance

A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate region approximately 50 kb downstream of the Endothelin 3 (EDN3) gene. EDN3 and other endothelin family members are associated with blood pressure regulation in humans and other species, but similar association studies in horses are lacking. We hypothesized that the sweep region includes a regulatory element acting on EDN3 transcription, ultimately affecting blood pressure regulation and athletic performance in horses. Selective sweep fine- mapping identified a 5.5 kb haplotype of 14 SNPs shared within Coldblooded trotters (CBT) and Standardbreds (SB). Most SNPs overlapped potential transcription factor binding sites, and haplotype analysis showed significant association with all tested performance traits in CBTs and earnings in SBs. From those, two haplotypes were defined: an elite performing haplotype (EPH) and a sub-elite performing haplotype (SPH). While the majority of SNPs in the haplotype were part of the standing variation already found in pre-domestication horses, there has been an increase in the frequencies of the alternative alleles during the whole history of horse domestication. Horses homozygous for EPH had significantly higher plasma levels of EDN3, lower levels of EDN1, and lower exercise-related blood pressure compared to SPH homozygous horses. Additionally, a global proteomic analysis of plasma from EPH or SPH homozygous horses revealed higher levels of proteins involved in pathways related to immune response and complement activation in the SPH horses. This is the first study to demonstrate an association between the EDN3 gene, blood pressure regulation, and athletic performance in horses. The results advance our understanding of the molecular genetics of athletic performance, exercise-related blood pressure regulation, and biological processes activated by intense exercise. Author summaryThe horse is one of the most common species used for studying athletic performance. For centuries, horses have been used by humans for transportation, agriculture and entertainment and this has resulted in selection for various traits related to athletic performance. A previous study discovered that a genetic region close to the Endothelin3 gene was associated with harness racing performance. Endothelin3 is known to be involved in blood pressure regulation and therefore we hypothesized that this region influences blood pressure and racing performance in horses. In this study we have used additional horses and fine-mapped the candidate region and we also measured blood pressure in Coldblooded trotters during exercise. Horses with two copies of the elite-performing haplotype had higher levels of Endothelin3 in plasma, lower blood pressure and better racing performance results, compared to horses with two copies of the sub-elite performing haplotype. We also discovered that horses with the sub-elite performing haplotype had higher levels of proteins related to the immune system in plasma. This study is the first to link Endothelin3 to blood pressure regulation and performance in horses. It broadens the understanding of the biological mechanisms behind blood pressure regulation as well as inflammation and coagulation system in relation to racing performance.

genetics↗

bioRxiv2020

Embryo-like features in developing Bacillus subtilis biofilms

Correspondence between evolution and development has been discussed for more than two centuries1. Recent work reveals that phylogeny-ontogeny correlations are indeed present in developmental transcriptomes of eukaryotic clades with complex multicellularity2-10. Nevertheless, it has been largely ignored that the pervasive presence of phylogeny-ontogeny correlations is a hallmark of development in eukaryotes6, 10-12. This perspective opens a possibility to look for similar parallelisms in biological settings where developmental logic and multicellular complexity are more obscure13-16. For instance, it has been increasingly recognized that multicellular behaviour underlies biofilm formation in bacteria13, 14, 17-19. However, it remains unclear whether bacterial biofilm growth shares some basic principles with development in complex eukaryotes14-16, 18, 20. Here we show that the ontogeny of growing Bacillus subtilis biofilms recapitulates phylogeny at the expression level. Using time-resolved transcriptome and proteome profiles, we found that biofilm ontogeny correlates with the evolutionary measures, in a way that evolutionary younger and more diverged genes were increasingly expressed towards later timepoints of biofilm growth. Molecular and morphological signatures also revealed that biofilm growth is highly regulated and organized into discrete ontogenetic stages, analogous to those of eukaryotic embryos11, 21. Together, this suggests that biofilm formation in Bacillus is a bona fide developmental process comparable to organismal development in animals, plants and fungi. Given that most cells on Earth reside in the form of biofilms22 and that biofilms represent the oldest known fossils23, we anticipate that the widely-adopted vision of the first life as a single-cell and free-living organism needs rethinking.

evolutionary biology↗