Alternative sources of dopaminergic neurons for cell replacement therapy in Parkinson's disease

Degeneration of mDA neurons is associated with Parkinson's disease (PD), one of the most common human neurological disorders. Previous studies using fetal grafts in PD patients have indicated that cell replacement therapy can result in significant symptomatic relief. However, this treatment is often associated with the development of serious side-effects eventually caused by the concomitant transplantation of non-DA neurons. Therefore, it has been suggested that a highly selective source of DA neurons would provide a better clinical outcome. In fact, embryonic stem (ES) cell-derived DA neurons have shown to be efficient in restoring motor symptoms when transplanted in PD animal models. However, the use of pluripotent derived cells might lead to the generation of tumors if not proper ly controlled. Thus, the development of alternative approaches to generate DA neurons independently by stem cells might represent an interesting opportunity. Lineage-specific transcription factors, which drive cellular identity during embryogenesis, have been shown to convert cell fate when expressed ectopically in heterologous cells, without passing through a proliferating step. Herein, we screened the key molecular factors governing the dopaminergic (DA) neuronal specification during brain development for their ability to generate functional neurons directly from mouse and human fibroblasts. Remarkably, we found a minimal set of three factors Ascl1, Nurr1 and Lmx1a able to elicit such cellular reprogramming. Molecular and transcriptome studies showed that reprogrammed DA neuronal cells recapitulate gene expression of their brain homolog cells. Induced DA neuronal (iDAN) cells released DA and showed spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain DA neurons [1]. Generation of iDAN cells from somatic cells might have significant implications in studies of neural development, disease in vitro modeling and cell replacement therapies.