Albena Jordanova

Research focus

The Albena Jordanova Lab focuses on the identification and characterization of genes and pathways implicated in the molecular etiology of inherited neurological disorders, like motor and sensory peripheral neuropathies and spastic paraplegias. This is our way to understand the molecular pathomechanisms and design strategies for prevention and treatment of these devastating diseases. The research strategy is not limited to one experimental approach, but starts with genetic studies in unique collections of patients and extends to model systems, like Drosophila, yeast or human cells.

The main research projects are:
• Identification of novel causative genes for inherited forms of peripheral neuropathies and spastic paraplegias using family and population based genetic approaches;
• Neurogenetics studies in the Gypsy population;
• Unraveling the role of aminoacyl-tRNA synthetases in degeneration of peripheral nerves;

Hereditary motor and sensory peripheral neuropathies (known also as Charcot-Marie-Tooth disease, CMT) and hereditary spastic paraplegias (HSP) are rare but severe neurological disorders found in all ethnic groups. They are currently untreatable, justifying further research on their etiology. We aim to better understand the molecular basis of CMT and HSP by finding causative genes and regulatory networks contributing to their pathology, as this knowledge offers particular translational opportunities. A unique entry point of our studies are large collections of nuclear families, where consanguinity or ethnic/geographic origin facilitates gene discovery. Using genetic approaches for mapping of human disorders combined with the most recent advances in next-generation sequencing and bioinformatics technologies, we create a powerful tool for gene identification. The causality of identified mutations and the triggered molecular pathomechanisms are further tested in appropriate cellular and animal models.

A specific population where we perform neurogenetics studies is the Gypsy founder population. Referred to as “the invisible minority”, Gypsies represent the largest transnational genetic and socio-cultural isolate of Europe. Studying their unique genetic heritage enables us to identify novel disease entities, to perform genotype-phenotype correlations in genetically homogeneous groups of patients and to tackle genetically and clinically heterogeneous neurological disorders.

Our research contributed to the recent recognition of aminoacyl-tRNA synthetases as important players in neurodegeneration. These enzymes are ubiquitously expressed and essential proteins, involved in the initial steps of protein biosynthesis and therefore indispensable for cell survival. We first reported that specific mutations in the tyrosyl-tRNA synthetase (TyrRS, YARS) cause Dominant Intermediate Charcot-Marie-Tooth disease type C (DI-CMTC) - a genetic and phenotypic variant of inherited peripheral neuropathy. TyrRS, along with GlyRS, AlaRS, LysRS, MetRS and HisRS comprise a newly discovered and important cluster of proteins associated with CMT neuropathies. It is enigmatic how mutations in these primordial enzymes can lead to a peculiar specificity of the pathophysiological deficit, characterized by axonal degeneration of the peripheral nerves only. We were the first to establish that the DI-CMTC phenotype is not due to haploinsufficiency of TyrRS enzymatic activity, but to a gain-of-function alteration of the mutant YARS or interference with an unknown function of the wild type protein. To unravel the alternative function of YARS in the nervous system we developed the first Drosophila model for inherited peripheral neuropathy, as well as appropriate cellular and yeast models. We apply gain-of-function modifier screens to identify genes modulating the neuron-specific phenotypes in the DI-CMTC flies. The putative modifier genes are functionally characterized using genetic, behavioural, electrophysiological, morphological and molecular biological experimental paradigms with the goal to understand the crucial cellular pathways affected by mutant YARS and how this contributes to neurodegeneration. We further search for common and specific neurodegenerative pathways between YARS and the other tRNA synthetases implicated in CMT disease.