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Molecular Neurobiology

Vanja Nagy, Molecular Neurobiology

phone: +43-1-40160-70093
email: vanja [dot] nagyatrud [dot] lbg [dot] ac [dot] at

 

Our team focuses on identification and characterization of novel causative genes in rare neurodevelopmental disorders. These studies are essential in understanding how dysfunctions manifest in neurological pathologies for development of efficient and personalized therapeutic agents. In close collaboration with clinicians, we perform whole-exome sequencing of patient samples to prioritize potentially deleterious genetic variants. We then use genetically modified human cell lines, transformed human neurons, primary mouse cultures and mouse models to validate and understand the identified genetic defects. Our current projects are listed below.

Identifying common molecular mechanisms underlining intellectual disabilities
Intellectual disability (ID), diagnosed as impairment in intellectual and adaptive function, is a common manifestation in NDDs which affects up to 3% of the human population. Over 1000 different genetic loci have been identified to be causative of monogentic forms of ID, with as many more predicted. In order to identify common molecular pathways in different IDs we use a rational systems-based approach to predict novel ID causative genes and their interaction networks, perform functional CRISPR-based genetic screens, and validate in primary mouse neuronal cultures and patient-derived transformed neurons. Validating genes of unknown significance will facilitate diagnosis of newly discovered potentially pathological genes in ID. Additionally, finding common nodes in different pathologies will allow for development of therapeutic interventions for groups of rare disorders sharing common pathways.

Spastic paraplegia with psychomotor retardation with or without seizures
A mutation in HACE1 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 HACE1 knock-out mice have a remarkably similar phenotype to patients and are an ideal model to study the molecular neuropathology of this disease. Using genetic and pharmacological manipulations of human and mouse cellular models of this disease, we are identifying and characterizing the molecular pathology and potential therapeutic targets of this disease.

Understanding peripheral neuropathies
Congenital insensitivity to pain with anhidrosis (CIP/A) is an inherited and rare type of peripheral neuropathy marked by a complete absence of pain perception. Using patient derived cells and various mouse models of CIP/A we are performing deep behavioral and molecular phenotyping of peripheral nervous system dysfunctions, and its contribution to non-nociceptive symptoms associated with this disorder. By deciphering the pathophysiology of this rare disorder we aim to identify potential targets for future therapy relevant to more common pathologies, such as chronic pain conditions that affect up to 30% of the population. 

Photo credit - CeMM/WDäuble