Project ID NS-MH2023_06


Co Supervisor 1A IoPPN/Basic and Clinical NeuroscienceWebsite

Co Supervisor 1B IoPPN/Basic and Clinical Neuroscience & Psychosis CAGWebsite

Investigating the role of mitochondrial dysfunction in neuropsychiatric disorders

Mitochondria generate ATP, play key roles in cellular metabolism and are essential for neuronal function. Increasing evidence points to a central role of mitochondria in the aetiology of neuropsychiatric disorders, including schizophrenia, depression and anxiety. 22q11.2 deletion syndrome is one of the most common genetic risk factors for schizophrenia and is strongly associated with mitochondrial dysfunction and abnormal dopamine neurotransmission.

We will focus on MRPL40, a key mitochondrial ribosomal gene within the 22q11.2 deletion syndrome region. The project will use human iPSC models and Drosophila to determine the mechanisms by which loss of MRPL40 causes imbalances in the dopamine system leading to increased risk for schizophrenia. Drosophila provides a fast, genetically tractable means to model neuropsychiatric-associated neuronal alterations and associated behaviours. Human iPSC derived neurons will be used to validate the Drosophila studies and analyse cellular and molecular changes. The overarching objectives are:

Year 1 (or rotation): Neuropsychiatric-related circadian rhythm, sleep, appetite and thigmotaxis assays in flies with dopaminergic network knockout of MRPL40; imaging of neuronal activity and synaptic architecture.

Year 2: Analysis of mitochondrial, cellular and molecular changes in MRPL40 knockout iPSC derived dopaminergic neurons and mitochondrial stress signalling pathways in iPSC derived neuron and Drosophila models.

Year 3: Testing potential therapeutic strategies to prevent neuropsychiatric associated phenotypes in Drosophila and iPSC MRPL40 knockout models.

The student will be trained in cutting edge Drosophila genetics and behavioural analysis, generation of iPSC derived neurons, molecular techniques, confocal and super resolution imaging by experienced members of the Bateman and Vernon labs.

Representative Publications

R.J. Hunt, L. Granat, G.S. McElroy, R. Ranganathan, N.S. Chandel, J.M. Bateman (2019). Mitochondrial stress causes neuronal dysfunction via an ATF4-dependent increase in L-2-hydroxyglutarate. J. Cell Biol. 218: 4007-4016.

Reid MJ, Rogdaki M, Dutan L, Hanger B, Sabad K, Nagy R, Adhya D, Baron-Cohen S, McAlonan G, Price J, Vernon AC, Howes OD, Srivastava DP. Cell line specific alterations in genes associated with dopamine metabolism and signaling in midbrain dopaminergic neurons derived from 22q11.2 deletion carriers with elevated dopamine synthesis capacity. Schizophr Res. 2022: S0920-9964(22)00184-0. doi: 10.1016/j.schres.2022.05.010. Epub ahead of print. PMID: 35701280