Mitochondrial optic neuropathies result in blindness and are currently untreatable. They arise as a consequence of genetic mutations in either mitochondrial or nuclear DNA and share the common characteristic of primarily affecting retinal ganglion cell (RGC) survival. We have demonstrated that prior to RGC loss there is a period of dysfunction and morphological change to the cellular architecture.
In this project we plan to utilise ultra-high resolution multi-electrode array to evaluate the functional consequences of mitochondrial dysfunction in cells in culture- primary mouse hippocampal cells and mouse RGCs and retinal explants. We will use mouse primary retinal dissociated culture, panned RGCs and explants from mouse models of mitochondrial dysfunction (both genetic and drug-induced) or h iPSCells. We will explore the effect of Opa1 mutation on electrical activity. We will explore the therapeutic effect of treatment with novel ubiquinone structures and other novel therapeutic strategies on the electrical activity of RGCs. We know that we can up-regulate of oxidative phosphorylation using therapeutic agents, but does this lead to improved or rescued electrical activity or function in RGCs? Ultimately, we want to establish if we can prevent or delay cellular dysfunction prior to the structural changes that take place which lead to loss of RGCs in mitochondrial optic neuropathies.
We aim to evaluate the earliest functional consequences of therapies for mitochondrial dysfunction on cells and retinal explants using electrical activity as an output. The overarching outcome of the project will be the establishment of a pipeline for the evaluation of the novel therapeutic interventions on RGC function and this read-out will be invaluable in directing further work on therapy for mitochondrial optic neuropathy.
We hypothesise that up-regulation of oxidative phosphorylation using therapeutic agents can prevent or delay the onset of cellular dysfunction, which occur prior to structural changes and loss of RGCs in mitochondrial optic neuropathies. We want to validate the ultra-high resolution multi-electrode array as a highly sensitive ex vivo output to detect the very earliest dysfunction in mitochondrial optic neuropathy and hence as a highly sensitive tool for monitoring therapeutic benefit.
Primary, inherited mitochondrial optic neuropathies, such as Leber’s hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA)) are a significant cause of visual impairment with no current cure (Yu Wai Man et al., 2014, Klopstock et al., 2011). They share mitochondrial dysfunction in the pre-laminar optic nerve and selective damage and loss of retinal ganglion cells (RGCs). Both LHON and ADOA share striking pathological similarities, marked by the early involvement of the papillomacular bundle. Three mitochondrial DNA (mtDNA) point mutations; m.3460G>A, m.11778G>A, and m.14484T>C account for over 90% of LHON cases, and in ADOA, the majority of affected families (70%) harbour mutations in the OPA1 nuclear gene, which codes for a mitochondrial inner membrane protein.
The retinal ganglion cell at the heart of mitochondrial optic neuropathy
Retinal ganglion cells (RGCs) are particularly susceptible to damage caused by reduced mitochondrial function. They first become dysfunctional and then die, by apoptosis, which then leads to blindness. However, as in many other neurodegenerative diseases, neuronal death is preceded by a prolonged period of dysfunction and cellular remodelling. Indeed, this period of dysfunction may be reversible with therapeutic intervention and may be the explanation behind the apparently mysterious spontaneous recovery of vision occasionally seen in patients with LHON. To date our research has characterised the earliest morphological changes as a progressive loss of synapses, dendrite retraction and RGC remodelling (Williams et al, 2010; Williams et al, 2012). These changes precede the terminal phase of apoptotic cell death.
Applicants should apply to the Doctor of Philosophy in Vision Sciences with a start date of 1st Oct 2022.
In the research proposal section of your application, please specify the project title and supervisors of this project and copy the project description in the text box provided. In the funding section, please indicate whether you wish to fund your studies yourself, you plan on applying to a specific funder, or you are applying for a studentship advertised by Cardiff University (please specify the name of the studentship). Please also include:
- an up-to-date CV
- a personal statement
- details of two referees