RePuRposing Of MemantIne as treatment for dopamine tranSporter dEficiency syndrome

Description

Submit your application : https://cometowallonia.eu/

Submit your application : https://cometowallonia.eu/

Dopamine Transporter Deficiency Syndrome (DTDS) is a rare genetic disease affecting children with a deficit in the Dopamine Transporter (DAT), a protein regulating the homeostasis of dopamine (DA) in the central nervous system and modulating motor control. These children present very severe and disabling motor symptoms appearing from early infancy and worsening throughout childhood; of note, very rarely they reach adulthood. At present, no effective treatments are available for this disorder highlighting a major unmet need for novel approaches that target the primary pathophysiological mechanisms.
Animal models do provide the advantage to reveal mechanisms in depth using invasive methods that ethically cannot be applied to humans. Our research consortium has multi-year experience in the study of a genetically modified animal model lacking, totally or partially, the DAT, i.e. the protein found to be defective in DTDS patients. Strikingly, mutant animals replicate major symptoms found in children with DTDS, thus providing an excellent experimental tool for the identification of novel pathophysiological pathways.

The working hypothesis of the project relies on the unbalance between the dopamine and glutamate systems and the idea that glutamate homeostasis could be altered in disorders characterized by impaired functions of the DAT. This possibility is indeed intriguing since the opposing roles of synaptic and extra-synaptic NMDA receptors on neuronal fate are well known, with synaptic NMDA receptors inducing a coordinate upregulation of pro-survival genes and downregulating pro-death genes whereas extra-synaptic NMDA receptors fail to activate this neuroprotective program, but instead their activation causes neurodegeneration and cell death.

We propose to use electrophysiological techniques, behavioral assessment and molecular tools to investigate this hypothesis.