A novel cell-permeable peptide prevents protein SUMOylation and supports the mislocalization and aggregation of TDP-43.

SUMOylation is a post-translational modification (PTM) that exerts a regulatory role in different cellular processes, including protein localization, aggregation, and biological activities. It consists of the dynamic formation of covalent isopeptide bonds between a family member of the Small Ubiquitin Like Modifiers (SUMOs) and the target proteins. Interestingly, it is a cellular mechanism implicated in several neurodegenerative pathologies and potentially it could become a new therapeutic target; however, there are very few pharmacological tools to modulate the SUMOylation process. In this study, we have designed and tested the activity of a novel small cell-permeable peptide, COV-1, in a neuroblastoma cell line that specifically prevents protein SUMOylation. COV-1 inhibits UBC9-protein target interaction and efficiently decreases global SUMO-1ylation. Moreover, it can perturb RanGAP-1 perinuclear localization by inducing the downregulation of UBC9. In parallel, we found that COV-1 causes an increase in the ubiquitin degradation system up to its engulfment while enhancing the autophagic flux. Surprisingly, COV-1 modifies protein aggregation, and specifically it mislocalizes TDP-43 within cells, inducing its aggregation and co-localization with SUMO-1. These data suggest that COV-1 could be taken into future consideration as an interesting pharmacological tool to study the cellular cascade effects of SUMOylation prevention.

The effect of two different Individually Ventilated Cage systems on anxiety-related behaviour and welfare in two strains of laboratory mouse.

The environment in which a laboratory animal is housed can significantly influence its behaviour and welfare, acting as a potential confounding factor for those studies in which it is utilised. This study investigated the impact of two Individually Ventilated Cage (IVC) housing systems on anxiety-related behaviour and welfare indicators in two common strains of laboratory mice. Subjects were juvenile female C57BL/6J and BALB/c mice (N=128) housed in groups of four in two different IVC systems for 7weeks. System One had air delivery at the cage 'cover' level at 75 ACH (Air Changes/Hour) and System Two had air delivery at the 'animal' level at 50 ACH. Mice were assessed twice a week (e.g. bodyweight) or at the end of the study (e.g. anxiety tests). Our results showed significant differences in anxiety-related behaviour between strains and housing systems. Mice in System Two, regardless of strain, defecated more in the Elevated Plus Maze (EPM), spent less time in the open arms of the EPM, and less time in the central zone of the Open Field (OF). Strain differences in anxiety-like behaviour were seen in the increased defecation by BALB/c mice in the OF and EPM and less time spent in the open arms of the EPM compared to C57BL/6J mice. These results suggest that different IVC housing systems can influence mouse behaviour in different ways, with mice of both strains studied exhibiting more anxiety-related behaviour when housed in System Two (air entry at the 'animal' level at 50 ACH), which could impact upon experimental data.