Biology subjects

Ganser, L.

Publications and source records attributed to Ganser, L..

3 recordsLinked to original sources

bioRxiv2023

Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains

RNA-binding proteins with prion-like domains, such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs (24-48 nucleotides) that prevent FUS fibrillization by promoting liquid phases, and distinct short RNAs that prevent and, remarkably, reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. Importantly, we define a short RNA that dissolves aberrant cytoplasmic FUS condensates, restores nuclear FUS, and mitigates FUS proteotoxicity in optogenetic models and human motor neurons. Another short RNA dissolves aberrant cytoplasmic TDP-43 condensates, restores nuclear TDP-43, and mitigates TDP-43 proteotoxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have therapeutic utility for ALS/FTD and related disorders.

biochemistry↗

bioRxiv2023

Linking folding dynamics and function of SAM/SAH riboswitches at the single molecule level

Riboswitches are found in the 5-UTR of many bacterial mRNAs. They function as cisacting regulatory elements that control downstream gene expression through ligand-induced conformational changes. Here, we used single-molecule FRET to map the conformational landscape of the SAM/SAH riboswitch and probe how co-transcriptional ligand-induced conformational changes of this translational switch alter ribosome accessibility. The folding of the riboswitch is highly heterogenous, indicating a complex and rugged conformational landscape that enables sampling of the ligand-bound conformation even in the absence of the ligand. Upon ligand binding, the landscape shifts towards the ligand-bound conformation. Mutations at key stabilizing structures alter the ligand-free folding behavior and decrease ligand responsiveness. We also explored translational regulation through folding kinetics by utilizing short oligonucleotides to probe the accessibility of the Shine-Dalgarno sequence within the riboswitch. Additionally, we employed a helicase-based vectorial folding assay to simulate co-transcriptional folding. We find that a competition between ligand binding and ribosome binding is fined tuned via the kinetics of folding. During transcription, the riboswitch takes minutes before reaching equilibrated conformations, and such slow equilibration decreases the effective ligand affinity. Overall, our data demonstrate the significance of conformational polymorphism in RNA function, emphasizing the utilization of complex folding landscapes for regulating ribosome accessibility through ligand induction. Furthermore, we provide direct evidence on how folding kinetics modulate this regulation process.

biophysics↗

bioRxiv2020

The brain's hedonic valuation system's resting-state connectivity predicts weight loss and correlates with leptin

Weight gain is often associated with the pleasure of eating foods rich in calories and lack of willpower to reduce such food cravings, but empirical evidence is sparse. Here we investigated the role that connectivity within the brains hedonic valuation system (BVS, the ventral striatum and the ventromedial prefrontal cortex) at rest plays (1) to predict weight gain or loss over time and (2) for homeostatic hormone regulation. We found that intrinsic connectivity within the BVS at rest (RSC) predicted out-of-sample weight changes over time in lean and obese participants. Counterintuitively, such BVS RSC was higher in lean versus obese participants before the obese participants underwent a drastic weight loss intervention (Roux-en-Y gastric bypass surgery, RYGB). The RYGB surgery increased BVS RSC in the obese after surgery. The obese participants increase in BVS RSC correlated with decreases in fasting state systemic leptin, a homeostatic hormone signalling satiety that has been previously linked to dopamine functioning. Taken together, our results indicate a first link between brain connectivity in reward circuits in a more tonic state at rest, homeostatic hormone regulation involved in dopamine functioning and ability to lose weight. Significance statementWith obesity rates on the rise, advancing our understanding of what factors drive peoples ability to lose and gain weight is crucial. This research is the first to link what we know about the brains hedonic valuation system (BVS) to weight loss and homeostatic hormone regulation. We found that connectivity at rest (RSC) within the BVS system predicted changes in weight, differentiated between lean and obese participants, and increased after a weight loss intervention (gastric bypass surgery). Interestingly, the extent to which BVS RSC improved after surgery correlated to decreases in circulating levels of the satiety hormone leptin. These findings are the first to reveal the neural and hormonal determinants of weight loss, combining hedonic and homeostatic drivers of (over-)eating.

neuroscience↗