Detail

Keywords

Drosophila melanogaster; Epilepsy; Folding and targeting of neurotransmitter transporters and GPCRs; Genetic Variation; Intellectual Disability; Molecular Mechanisms of Pharmacological Action; Mutation, Missense; Neuropharmacology; Neuropsychopharmacology; Neurotransmitter Transporters; Neurotransmitter Uptake Inhibitors; Parkinsonian Disorders; Protein Folding

Research interests

The main focus of research in my laboratory are rare disease variants occurring in human neurotransmitter transporter (NTT) genes. We explore not only the functional consequences, but also the molecular aspects (e.g. protein folding and trafficking), of NTT mutations linked to a wide range of pathological conditions in people (e.g. autism, epilepsy, infantile parkinsonism & intellectual disability). We also investigate different novel therapeutic avenues, applicable in the pharmacological rescue of such disease variants, i.e. via treatment of cell lines and Drosophila melanogaster (fruit flies) with small molecules known as chemical/pharmacological chaperones & allosteric modulators. Other ongoing projects in my group deal with structure-activity relationship (SAR) studies of monoamine transporters, in particular their interactions with antidepressant and psychostimulant drugs.

Techniques, methods & infrastructure

Pharmacological assays (radioligand uptake, binding and efflux experiments), molecular biology and biochemistry (site-directed mutagenesis, DNA/RNA purifications, cell surface biotinylation, immunoblotting, immunocytochemistry), cell culture (primary neuronal cultures, established cell lines, transient and stable transfections, siRNA-induced gene knockdown etc), microscopy (confocal laser scanning microscopy and förster resonance energy transfer (FRET), studies investigating transporters and mutants thereof in fruit flies (Drosophila melanogaster).  

Grants

• GAT-1 variants in epilepsy: molecular and rescue mechanisms (2022)
  Source of Funding: FWF (Austrian Science Fund), Stand-alone project
  Principal Investigator
• Pharmacological rescue of creatine transporter-1 variants (2018)
  Source of Funding: FWF (Austrian Science Fund), Stand-alone project
  Principal Investigator
• Pharmacochaperoning of the dopamine transporter (2014)
  Source of Funding: FWF (Austrian Science Fund), Stand-alone project
  Principal Investigator
• Molecular structure-function relationship studies of the human noradrenaline transporter (2001)
  Source of Funding: Australian Federal Government, Department of Education and Training, Australian Postgraduate Awards (APA)
  Principal Investigator

Selected publications

1. Kasture, A.S. et al., 2023. Drosophila melanogaster as a model for unraveling unique molecular features of epilepsy elicited by human GABA transporter 1 variants. Frontiers in Neuroscience, 16. Available at: https://www.frontiersin.org/articles/10.3389/fnins.2022.1074427/full.
2. Fischer, F.P. et al., 2022. Molecular and Clinical Repercussions of GABA Transporter 1 Variants Gone Amiss: Links to Epilepsy and Developmental Spectrum Disorders. Frontiers in Molecular Biosciences, 9. Available at: https://www.frontiersin.org/articles/10.3389/fmolb.2022.834498/full.
3. Bhat, S. et al., 2021. Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits. Pharmacology & Therapeutics, 222, p.107785. Available at: http://dx.doi.org/10.1016/j.pharmthera.2020.107785.
4. Farr, C.V. et al., 2020. The Creatine Transporter Unfolded: A Knotty Premise in the Cerebral Creatine Deficiency Syndrome. Frontiers in Synaptic Neuroscience, 12. Available at: http://dx.doi.org/10.3389/fnsyn.2020.588954.
5. El-Kasaby, A. et al., 2019. Rescue by 4-phenylbutyrate of several misfolded creatine transporter-1 variants linked to the creatine transporter deficiency syndrome. Neuropharmacology, 161, p.107572. Available at: http://dx.doi.org/10.1016/j.neuropharm.2019.03.015.