Investigating the role of mitochondrial dysfunction in neurometabolic disorders

Background:
Defective mitochondrial function can lead to abnormal brain development as well as post-natal disorders. Mitochondria are the power house of the cell, functioning to  generate energy and also biochemicals that are essential for growth and survival. These are crucial during neural tube (precursor of the brain and spinal cord) development in embryonic stages as well as early postnatal brain development. The project will make use of targeted cell lines and novel transgenic mouse models carrying a deficient mitochondrial protein (glycine decarboxylase or Gldc) mutations of which have been found to cause serious neuro-metabolic disorders in humans. These human mutations can lead to disorders at three different stages of brain development - neural tube defects in the early embryo, hydrocephalus at later embryonic stages and non-ketotic hyperglycinemia, a post-natal condition. These disorders reflect cell- and tissue-specific functions of Gldc whose expression changes during development progression. Demand for mitochondrial function also varies through these stages in development so this period will help us to understand how mitochondrial dysfunction in specific cells or tissues at particular time-points leads to alterations in brain development. In turn, this will inform the development and evaluation of new treatments.

Aims/Objectives:
The aim of the project is (1) to use Gldc-loss of function models to understand the involvement of mitochondrial dysfunction in abnormal brain development during embryonic and early post-natal stages; (2) to investigate the effects of abnormal mitochondria on gene expression (e.g. pathogenic and/or compensatory changes) and cellular functions; (3) to ask whether targeted treatments can restore development of particular groups of cells and/or brain regions.  

Methods:
The successful student will join a multi-disciplinary research group using a range of technologies, which will allow a flexible approach in which the project focuses on areas to fit the interests of the student. The project will use in vitro cell culture of patient cell lines (iPSCs) and in vivo mouse models, in which the causative genes have been disrupted and/or replaced by expression reporters. Core methods will include cell culture, use of advanced mouse genetic models and imaging using light and fluorescent confocal microscopy, with a range of technologies and analysis tools. Functional studies may include Seahorse analysis of mitochondrial function, mass spectrometry analysis of specific biochemicals, and gene expression analysis using RNA-seq and bioinformatic tools.

References:

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4. Leung KY et al. J Inherit Metab Dis. 43:1186-1198 (2020) 
5. Leung KY et al. Front Genet. 2021 Jan 25;12:625120