- Kaan Boztug (Director LBI-RUD)
- Thijn Brummelkamp (CeMM)
- Georg Busslinger Group (CeMM)
- Robert Kralovics Group (CeMM)
- Joanna I. Loizou Group (CeMM)
- Nuno Maulide (CeMM)
- Jörg Menche (CeMM)
- Vanja Nagy (LBI-RUD)
- Thomas Reiberger (LBI-RUD/CeMM)
- Georg Stary (LBI-RUD/CeMM)
- Davide Seruggia (CCRI/CeMM)
- Miriam Unterlass (CeMM)
- Andreas Villunger (CeMM/LBI-RUD)
CeMM Adjunct Principal Investigator
Development, function and pathology of the nervous system
The long term goal of our research group is to identify and characterize novel genes that underlie development, function and pathologies of the nervous system. To this end, we focus on the genetic basis of rare disorders in humans, and use a multidisciplinary approach including behavioral studies, imaging and molecular/biochemical assays in animal models to study different genetic mutations and understand how they contribute to human pathology. The identification of novel genes and elucidation of their regulatory networks are essential in understanding how dysfunctions manifest themselves in neurological pathologies, and to harness those discoveries for the development of efficient therapeutic agents.
Understanding peripheral neuropathies
Congenital insensitivity to pain with anhidrosis (CIPA) is an inherited and rare type of peripheral neuropathy marked by a complete absence of pain perception. By deciphering the pathophysiology of this disease and characterizing the key molecular players, we aim to provide novel targets for future therapy. While short-term sensation of pain has a beneficial and protective function, it can develop into a chronic pathological state, lasting for months to years. Although our understanding of the molecular mechanisms underlining nociceptive processing has progressed significantly, effective and non-habit forming therapeutics are still lacking. By detailed analysis of this family of disorders, we aim to identify novel therapeutic targets for pain management relevant for a larger population.
Synaptic plasticity underlying neurodevelopmental disorders
A synapse is a functional unit connecting two neurons, and in relevant regions of the brain is thought to be the epicenter of memory storage. So-called ‘synaptic plasticity’, the ability of the synapse to undergo substantial structural and functional remodeling indispensable for its function, is orchestrated by a molecular network of complex intra- and extracellular events. A posttranslational modification, ubiquitination, for example, has recently gained ground as an important event during learning-dependent synaptic activity. A mutation in one E3 ubiquitin ligase has been shown to cause a neurodevelopmental disorder resulting in intellectual disability, spasticity and abnormal gait in young patients. We find that mice lacking this ligase have a remarkably similar phenotype to patients and are an ideal model to study the molecular neuropathology of this disease.
Vanja Nagy joined the LBI-RUD as Key Researcher and CeMM as Adjunct PI in 2016. She obtained her PhD at the Icahn School of Medicine at Mount Sinai, USA and received postdoctoral training in the groups of Ivan Dikic and Josef Penninger. In the USA, she studied basic molecular neuroscience and described a novel role for extracellular proteolysis supporting structural and functional synaptic remodeling underlining learning and memory. In Austria, she focused on preclinical phenotyping of mouse models of genetic disorders affecting basic functions of the nervous system. At LBI-RUD, her group utilizes NGS technology to identify novel causative genes that underlie undiagnosed rare neurodevelopmental disorders, with a focus on intellectual disability and epilepsy. To gain insight into disease pathophysiology, her group applies a multidisciplinary approach: from behavioral phenotyping of genetic mouse models to detailed molecular and cellular characterization of both mouse and transdifferentiated patient neurons. This year, in close collaboration with Jörg Menche’s team, the group employed a network-based approach generated from known intellectual disability genes to identify common molecular pathways and the most likely novel causative genes that will be functionally validated in a cellular system. Together, these studies will uncover common therapeutic targets, predict genes deleterious to neuronal function, and shed light on the basic biology of the neuron.
Desiderio S*, Vermeieren S*, et al. Prdm12 directs nociceptive sensory neuron development by regulating the expression of the NGF receptor TrkA. Cell Rep. 2019 Mar 26;26(13):3522-3536.e5. (abstract)
Nagy V#, et al. HACE1 deficiency leads to structural and functional neurodevelopmental defects. NeurolGenet. 2019; 5(3). Co-corresponding author. (abstract)
Nagy V, et al. The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception. Cell Cycle. 2015;14(12):1799-1808. (abstract)
Nagy V, et al. The extracellular protease matrix metalloproteinase-9 is activated by inhibitory avoidance learning and required for long-term memory. Learn Mem. 2007;14(10):655-664. (abstract)