| The developing brain orchestrates the processes of cell division, migration, differentiation, neurite outgrowth and synaptogenesis with impressive precision. In response to damage the brain often re-expresses developmental cues as part of the recovery and repair process. Thus, we hypothesize that molecules involved in differentiation and growth of a neural system may provide clues relevant to its repair following injury or disease. This dissertation addresses this possibility for the nigrostriatal dopamine system. In support of this hypothesis we found that microarray examination of gene expression suggested an important role for the heparin binding growth factor family at selected time-points during initiation and maturation of dopaminergic innervation. Subsequent studies verified that the two related growth factors, midkine and pleiotrophin (PTN), and their receptors syndecan-3 and receptor protein tyrosine phosphatase beta/zeta (RPTPbeta/zeta) were highly expressed in the striatum during development. Furthermore, we found that PTN is up-regulated in the degenerating substantia nigra of patients with Parkinson's disease (PD). Relevant to the identification of novel therapeutic molecules, the addition of PTN to ventral mesencephalic cultures augmented dopamine (DA) neuron survival, function and neurite outgrowth. Therefore, PTN was identified as a factor that plays a role in the nigrostriatal system during development and in response to disease, and may therefore be useful for neuroprotection or reconstruction of the DA system. However, in a 6-hydroxydopamine rat model of PD, this study failed to show that PTN had any effects on DA graft survival or neurite outgrowth, when added to the cell suspension or when infused adjacent to a graft. Moreover, PTN-treated grafts did not promote functional recovery in excess of control-grafted animals. From this study we can conclude that a single bolus infusion of PTN adjacent to a ventral mesencephalic graft is not an effective strategy to augment cell replacement therapy for PD. |
