Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease and degeneration of the nigral dopamine neurons is a key pathological feature of the condition. PD is characterised by overt motor symptoms, such as rigidity and bradykinesia, as well as a wide range of non-motor symptoms, including dementia and apathy. The treatments available, or in development for PD, focus almost exclusively on alleviating the motor symptoms, despite the fact that the non-motor symptoms are frequently reported as affecting quality-of-life more than the motor symptoms.
In our lab, we work towards developing stem cell therapies for Parkinson’s disease, which involves the transplantation of live dopamine progenitor cells into the brain, to replace the cells lost to the disease. Cell therapies have already been shown to dramatically improve motor impairments in preclinical models and first-in-man clinical trials have just commenced in patients around the world.
In the process of investigating the effect of these cell transplants on non-motor dysfunctions, we identified some cell preparations that effectively alleviated cognitive deficits (fetal-derived cells), whilst others did not improve these symptoms (stem cell-derived cells). The most stark difference between these cell therapy products is that authentic fetal-derived grafts harbour a range of cell types, including both A9 and A10 dopamine subtypes, whilst stem cell-derived grafts are produced using differentiation protocols designed to enrich for A9 neurons.
The neural systems known to support cognitive function are predominately composed of A10 neurons with distinct networks emanating from ventral tegmental area to medial striatum, nucleus accumbens and prefrontal cortical regions. This makes it pertinent to reconsider and refine our understanding of the cell subtype composition necessary to produce the desired treatment efficacy. Thus, whilst enriching for A9 subtype works well for treating the most overt motor impairments, it may overlook the potential of this treatment to modulate other dopamine-dependent symptoms of the disease, including cognitive and neuropsychiatric dysfunctions.
Thus, we hypothesise that inclusion of A10 neurons within the transplant will optimise graft efficacy and specifically impact upon non-motor (cognitive, neuropsychiatric) functions. We propose that lentiviral over expression of Sox6 and Otx2 during the dopamine differentiation will drive development of more specified A9 and A10 dopamine subtypes, respectively. This hypothesise is supported by published data demonstrating continued expression of Otx2 in A10 neurons, as well as more direct evidence that Otx2-overexpressing stem cell-derived dopamine neurons preferentially innervate A10 target areas and reform biologically relevant neural networks.
The proposed study will address the following questions:
(i) To what extent does overexpression of Sox6 and Otx2 produce authentic A9 and A10 neurons, respectively?
(ii) Can inclusion of A10 dopamine neurons improve non-motor (cognitive) dysfunctions in a rodent model of PD?
(iii) Do A9 and A10 dopamine neurons establish distinct, biologically relevant synaptic networks within the basal ganglia?
The data generated by this project will be highly relevant to the field and have the potential to drive the development of second generation cell therapy products for PD.
*Please note that this project can be completed as an MPhil or PhD*
A 1st or Upper 2nd class UK honours degree or equivalent. Please visit School of Biosciences Postgraduate Research for more details.
For those whose first language is not English, IELTS with an overall score of 6.5 with 5.5 in all subskills, or equivalent. Please see our English Language Requirements guidance for more details.
How to Apply
To submit a formal application via Cardiff University’s online application service, click the 'Institution Website' button on this advert; in the ‘Apply’ box at the top-right of the page, select Qualification (Doctor of Philosophy/Master of Philosophy), Mode of Study (Full Time) and Start Date (this can be flexible as it is a self-funded project). This will take you to the application portal.
Candidates must submit the following:
• Supporting statement
• Qualification certificates
• Proof of English language (if applicable)
In the research proposal section of the application, specify the project title and supervisors of the project. In the funding section, specify that you will be self-funding. If you are applying for more than one Cardiff University project with the same entry intake, please note this in the research proposal section as the form only allows you to enter one title.