Inherited Manganese Transporter Defects
Manganese is an essential trace metal and critical for brain physiology and development. However, excess manganese is neurotoxic and leads to dystonia-parkinsonism, psychiatric and intellectual disability.
Our research has identified two manganese transporter defects associated with manganese neurotoxicity – hypermanganesaemia with dystonia 1 (HMNDYT1) and 2 (HMNDYT2). They are caused by loss-of-function mutations in SLC30A10 and SLC39A14, respectively, that encode manganese transporters that act in conjunction to mediate metal excretion. Manganese deposition in the brain leads to progressive, childhood-onset dystonia-parkinsonism associated with significant disability and premature death.
Our lab is part of Zebrafish research at UCL. We use manganese transporter mutant zebrafish as models for manganese overload/deficiency in order to dissect how metal dyshomeostasis disrupts neurons, synapses and circuit function with the view to identifying new therapeutic targets. In addition, we are working to develop a novel, orally bioavailable Mn chelator to improve treatment for disorders associated with Mn neurotoxicity.