Biology subjects

Bitsch, F.

Publications and source records attributed to Bitsch, F..

3 recordsLinked to original sources

bioRxiv2023

Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control

Suppression of premature termination codons (PTC) by translational readthrough is a promising strategy to treat a wide variety of severe genetic diseases caused by nonsense mutations. Here, we present two novel and potent readthrough promoters - NVS1.1 and NVS2.1 - that restore substantial levels of functional full-length CFTR and IDUA proteins in disease models for cystic fibrosis and Hurler syndrome, respectively. In contrast to other readthrough promoters that affect stop codon decoding, the NVS compounds stimulate PTC suppression by triggering rapid proteasomal degradation of the translation termination factor eRF1. Our results show that this occurs by trapping eRF1 in the terminating ribosome, causing ribosome stalls and subsequent ribosome collisions, activating a novel branch of the ribosome-associated quality control (RQC) network that involves the translational stress sensor GCN1 and the catalytic activity of the E3 ubiquitin ligases RNF14 and RNF25.

molecular biology↗

bioRxiv2020

Antagonism Between Brain Regions Relevant for Cognitive Control and Emotional Memory Facilitates the Generation of Humorous Ideas

The ability to generate humor gives rise to positive emotions and thus facilitate the successful resolution of adversity. Although there is consensus that inhibitory processes might be related to broaden the way of thinking, the neural underpinnings of these mechanisms are largely unknown. Here, we use functional Magnetic Resonance Imaging, a humorous alternative uses task and a stroop task, to investigate the brain mechanisms underlying the emergence of humorous ideas in 24 subjects. Neuroimaging results indicate that greater cognitive control abilities are associated with increased activation in the amygdala, the hippocampus and the superior and medial frontal gyrus during the generation of humorous ideas. Examining the neural mechanisms more closely shows that the downregulation of frontal brain regions is associated with an upregulation in the amygdala, which is concurrently linked with an increased number of humorous ideas and enhanced amygdala responses during the task. Our data therefore suggests that a neural antagonism previously related to the emergence and regulation of negative affective responses, is linked with the generation of emotionally positive ideas and may represent an important neural pathway supporting mental health.

neuroscience↗

bioRxiv2020

Characterizing the Theory of Mind Network in Schizophrenia Reveals a Sparser Network Structure

Impaired social functioning is a hallmark of schizophrenia and altered functional integration between distant brain regions are expected to account for signs and symptoms of the disorder. The functional neuroarchitecture of a network relevant for social functioning, the mentalizing network, is however poorly understood. In this study we examined dysfunctions of the mentalizing network in patients with schizophrenia compared to healthy controls via dynamic causal modelling and an interactive social decision-making game. Network characteristics were analyzed on a single subject basis whereas graph theoretic metrics such as in-degree, out-degree and edge-connectivity per network node were compared between the groups. The results point to a sparser network structure in patients with schizophrenia and highlight the dorsomedial prefrontal cortex as a disconnected network hub receiving significantly less input from other brain regions in the network. Further analyses suggest that integrating pathways from the right and the left temporo-parietal junction into the dorsomedial prefrontal cortex were less frequently found in patients with schizophrenia. Brain and behavior analyses further suggest that the connectivity-intactness within the entire network is associated with functional interpersonal behavior during the task. Thus, the neurobiological alterations within the mentalizing network in patients with schizophrenia point to a specific integration deficit between core brain regions underlying the generation of higher-order representations and thereby provide a potential treatment target.

neuroscience↗