Devine, MJ; (2012) Patient-derived cell models of Parkinson’s disease. Doctoral thesis , UCL (University College London).

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Abstract

Parkinson’s disease is the commonest neurodegenerative movement disorder. Although the pathological loss of dopaminergic neurons in the substantia nigra has long been recognised, the disease remains incurable because the mechanisms underlying this loss are not understood. Finding genes that cause inherited forms of the disease can help by pinpointing pathways that lead to neuronal death when faulty. However, analysis of these genes is complicated by the inaccessibility of diseased tissue during life. One possible solution is to use fibroblasts from patients, which retain pathogenic mutations and might act as a surrogate for diseased cells. But a major advance might be provided by reprogramming fibroblasts into induced pluripotent stem cells. These can be differentiated into multiple cell lineages, including those specific cells affected by disease. Here, two studies are described using fibroblasts from Parkinson’s disease patients with LRRK2 mutations. The first suggests that 4EBP, a component of the mTOR pathway, is hyperphosphorylated in patient fibroblasts. In contrast, the second study suggests that gene transcription is not significantly altered in these cells. To improve on this non-neuronal model, induced pluripotent stem cells were generated using fibroblasts from a Parkinson’s disease patient with triplication of the a-synuclein locus, alongside healthy controls. When these cells are differentiated into dopaminergic neurons, those from the patient have double dosage of a-synuclein protein, but only when clonal variation and efficiency of neuralisation are addressed. Nevertheless, these cells precisely recapitulate the cause of Parkinson’s disease in this kindred. These studies demonstrate the feasibility of generating cells of interest from a patient with a neurodegenerative disorder, but also highlight the inherent variability in induced pluripotent stem cell systems. These data emphasise the need for robust methods of neuronal differentiation, and the need to generate multiple induced pluripotent stem cell clones from each subject when developing such disease models.

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