Dopaminergic Neurogenesis: From Development to Stem Cell Replacement Therapies

Parkinson's disease is a devastating neurodegenerative disorder characterized by the loss of dopamine producing neurons (dopaminergic neurons) in a specific brain region, the ventral midbrain. The cells loss leads to the loss of dopamine in areas where these neurons project and to an inadequate control motor function. As the current therapies only lead to temporarily limited improvement, and have side effects, several new approaches to treat Parkinson's disease are being developed. A promising strategy consists on replacing the dead cells with new dopaminergic neurons, to overcome the cell loss and attenuate and even eliminate symptoms. Successful results have been obtained in several patients after transplantation of dopaminergic neurons isolated from human fetuses. However, the widespread use of this approach is limited by technical and ethical issues associated with the requirement of several fetuses to treat one patient. Stem cells are in this regard very promising therapeutic tools as one cell could be used to treat several patients and could be standardized for properties and quality. However, in order to be able to exploit all the therapeutic potential of stem cells we need to improve our understanding of how a dopaminergic neurons are made during development. Despite the great volume of research in this area there are still very important gaps in our knowledge that limit our capacity to develop effective stem cell replacement therapies for Parkinson's disease. One such a gap expands over a critical stage of development when neurogenesis, the process by which a stem cell makes a neuron, takes place. Neurogenesis is a well-studied process in other brain structures but surprisingly little is known about this process in relation to dopaminergic neurons. In the present study we propose to: (1) Identify the genes required for dopaminergic neurogenesis during development. (2) Express these genes in human neural stem cells and determine whether they can enhance the generation of dopaminergic neurons and exert therapeutic effects after transplantation in rodent models of Parkinson's disease.