ERC FUNDED PROJECTS

Familial forms of neurodegenerative diseases are caused by mutations in a single gene. It is unknown whether distinct mutations in the same gene or in functionally related genes cause disease through similar or disparate mechanisms. Furthermore, the precise molecular mechanisms underlying virtually all neurodegenerative disorders are poorly understood, and effective treatments are typically lacking. This is also the case for Charcot-Marie-Tooth (CMT) peripheral neuropathy caused by mutations in five distinct tRNA synthetase (aaRS) genes. We previously generated Drosophila CMT-aaRS models and used a novel method for cell-type-specific labeling of newly synthesized proteins in vivo to show that impaired protein translation may represent a common pathogenic mechanism. In this proposal, I aim to determine whether translation is also inhibited in CMT-aaRS mouse models, and whether all mutations cause disease through gain-of-toxic-function, or alternatively, whether some mutations act through a dominant-negative mechanism. In addition, I will evaluate whether all CMT-aaRS mutant proteins inhibit translation, and I will test the hypothesis, raised by our unpublished preliminary data shown here, that a defect in the transfer of the (aminoacylated) tRNA from the mutant synthetase to elongation factor eEF1A is the molecular mechanism underlying CMT-aaRS. Finally, I will validate the identified molecular mechanism in CMT-aaRS mouse models, as the most disease-relevant mammalian model. I expect to elucidate whether all CMT-aaRS mutations cause disease through a common molecular mechanism that involves inhibition of translation. This is of key importance from a therapeutic perspective, as a common pathogenic mechanism allows for a unified therapeutic approach. Furthermore, this proposal has the potential to unravel the detailed molecular mechanism underlying CMT-aaRS, what would constitute a breakthrough and a requirement for rational drug design for this incurable disease.

2 000 000 €

Start date: 2018-06-01, End date: 2023-05-31

The evolutionary arms race has optimized and shaped the way animals attend to relevant sensory stimuli in an ever-changing environment. This is a complex task, because the vast majority of sensory experiences are not relevant. In humans, attentional disorders are a serious public health concern because of its high prevalence, but its causes are mostly unknown. In this proposal, I will explore the neuronal mechanisms used by the nervous system to attend visual cues to enable appropriate behaviors. We will combine cutting edge imaging techniques, optogenetic interventions, behavioral read outs and targeted connectomics to study the neuronal transformations of the mouse Superior Colliculus (SC), an evolutionary conserved midbrain area known to process sensorimotor transformations and to be involved in the allocation of attention. First, this work will reveal a detailed description of visual representation in the SC, focusing on understanding how defined retinal information-streams, like motion and color, contribute to these properties. Second, we will characterize sensorimotor transformations instructed by the SC. The combination of the previous two objectives will determine mechanisms of visual saliency and sensory driven attention (“bottom-up” attention). Finally, we will explore the neuronal mechanisms of attention by studying the modulatory effect of higher brain areas (“top-down” attention) on sensory transformation and multisensory integration in the SC. Taken together, this proposal aims to understand principles underlying sensorimotor transformation and build a framework to study attention in health and disease.

1 446 542 €

Start date: 2017-12-01, End date: 2022-11-30

State-of-the-art simulations and observations highlight the self-organization of convective clouds. Our recent work shows two aspects: these clouds are capable of unexpected increase in extreme precipitation when temperature rises; interactions between clouds produce the extremes. As clouds interact, they organize in space and carry a memory of past interaction and precipitation events. This evidence reveals a severe shortcoming of the conventional separation into "forcing" and "feedback" in climate model parameterizations, namely that the "feedback" develops a dynamics of its own, thus driving the extremes. The major scientific challenge tackled in INTERACTION is to make a ground-breaking departure from the established paradigm of "quasi-equilibrium" and instantaneous convective adjustment, traditionally used for parameterization of "sub-grid-scale processes" in general circulation models. To capture convective self-organization and extremes, the out-of-equilibrium cloud field must be described. In INTERACTION, I will produce a conceptual model for the out-of-equilibrium system of interacting clouds. Once triggered, clouds precipitate on a short timescale, but then relax in a "recovery" state where further precipitation is suppressed. Interaction with the surroundings occurs through cold pool outflow,facilitating the onset of new events in the wake. I will perform tailored numerical experiments using cutting-edge large-eddy simulations and very-high-resolution observational analysis to determine the effective interactions in the cloud system. Going beyond traditional forcing-and-feedback descriptions, I emphasize gradual self-organization with explicit temperature dependence. The list of key variables of atmospheric water vapor, temperature and precipitation must therefore be amended by variables describing organization. Capturing the self-organization of convection is essential for understanding of the risk of precipitation extremes today and in a future climate.

1 314 800 €

Start date: 2018-07-01, End date: 2023-06-30

Mass demonstrations are newsworthy. But how are they remembered when they are no longer news? Social movements are usually studied in terms of their emergence and subsidence. Despite recognition that activists are ‘inspired’ by precedents, the afterlife of activism in story and image has never been systematically explored. ReAct contends that knowledge about this cultural memory is needed for a full understanding civil resistance. ReAct will provide the first in-depth account of the remembering and forgetting of activism in Europe since the late 19th century. It will reveal continuities and changes in how protest has been depicted in different media regimes; demonstrate the role of texts, images, and commemorative practices in conveying the memory of protest to later generations; and show how this memory feeds back into later movements at home and abroad. The project is designed around case studies from periods of heightened activism in Europe: 1871-1914; 1960-1970; 2011-2012. Work packages follow 3 intersecting lines of inquiry: mediation (what cultural frames have been used to turn activism into transferable knowledge?); afterlives (how has the memory of particular movements been culturally transmitted?); memoryscapes (how have later movements referenced earlier ones?). A key innovation is network visualization to map the reproduction of narratives and references to predecessors. ReAct will effect a major reorientation in cultural memory research: by developing analytic tools with which to capture the cultural transmission of hope, it provides an alternative to the trauma-based models that currently dominate the field. It will also open up a new area of social movement research by revealing traditions of civic memory and how it is culturally produced. Outside of the academy, ReAct will provide critical literacies with which to rethink collective memory and identity in terms of active citizenship rather than ethnic-national grievances.

2 498 750 €

Start date: 2019-01-01, End date: 2023-12-31