Abstract
Recent studies have suggested that bone marrow-derived stem cells offer protection to neurons via multiple and diverse actions. Furthermore, stem cell derived factors are able to improve some of the metabolic deficiencies seen in cell models of the progressive neurological condition Friedreich ataxia (FRDA), suggesting that transplantation or mobilisation of stem cells may be a potential therapy. Here we propose an exploration of the mechanisms by which bone marrow stem cell mobilising drugs may provide neuroprotection and influence regeneration in FRDA. We hypothesise that these drugs act via multiple mechanisms, with direct neuroprotective effects and secondary reparative effects through facilitation of neuronal regeneration by both intrinsic neural stem cells and mobilised bone marrow cells. We propose to use a combination of cell culture models and FRDA animal models. We will study direct neuroprotective effects of stem cell mobilising drugs on neuronal cultures and inducible pluripotent stem (iPS) cells derived from patients with FRDA. Differentiation of FRDA iPS cells into a neuronal phenotype will allow an analysis of the effect of these drugs on frataxin and mitochondrial signalling pathways. We will also use mouse models of FRDA and analyse the effects of administration of stem cell mobilising drugs. We will determine whether these drugs influence neuronal pathology and whether this is dependent on stem cell mobilisation. We will establish whether administration of these drugs increases entry of stem cells into the brain and whether these cells integrate with endogenous neurons. Using ex vivo cerebellar slices with electrophysiological and single cell PCR, we will determine whether integration of stem cells with endogenous cerebellar cells alters electrical properties or gene expression within the cerebellum. Understanding these therapeutic mechanisms will potentially allow the development of a novel neuroprotective therapy in patients with FRDA.