Moving Beyond Tyrosine Hydroxylase to Define Dopaminergic Neurons for Use in Cell Replacement Therapies for Parkinson’s Disease

Robert      B. White; Meghan      G. Thomas

Abstract

Cell replacement therapies are an attractive mode of treatment for neurodegenerative disorders as they have the potential to alleviate or modify disease symptoms and restore function. In Parkinson’s disease, the cell type requiring replacement is dopamine-producing neurons of the midbrain. The source of replacement cells is contentious, with opinion still evolving. Clinical trials have previously used fetal brain tissue; however, this will likely be superseded by the use of embryonic or induced pluripotent stem cells, due to their greater availability and homogeneity. One significant caveat in the use of any cell source for therapy is that cells must first be adequately characterised and purified. The gold standard marker in the identification of dopaminergic neurons is tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis, catalyzing the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine. However, there are multiple ways of measuring TH readout, and potential flaws in the fidelity of TH expression. This review will look at the complex regulatory mechanisms that govern different facets of TH expression, including reported differences in TH expression in vitro and in vivo. We will also examine the regulation of the TH gene; assessing the which, the where and the when of TH expression. We will look at how knowledge of regulation of the TH gene can be utilised to enhance research efforts. And, finally we will delve into the transcription factors that govern elements of TH expression, and which may prove more effective for defining appropriate dopaminergic neuron precursor cells.

Keywords: Cell replacement therapy, dopaminergic neuron, Nurr1, Parkinson’s disease, Pitx3, transcriptional regulation, Tyrosine hydroxylase.

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