Molecular manipulation targeting regulation of dopaminergicdifferentiation and proliferation of neural stem cells or pluripotent stemcells

Parkinson's disease (PD) is a severe deliberating neurological disease caused by progressive degenerative death ofdopaminergic neurons in the substantia nigra of midbrain. While cell replacement strategy by transplantation of neural stem cells andinducement of dopaminergic neurons is recommended for the treatment of PD, understanding the differentiation mechanism andcontrolled proliferation of grafted stem cells remain major concerns in their clinical application. Here we review recent studies onmolecular signaling pathways in regulation of dopaminergic differentiation and proliferation of stem cells, particularly Wnt/β-cateninsignaling in stimulating formation of the dopaminergic phenotype, Notch signaling in inhibiting stem cell differentiation, and Sonichedgehog functioning in neural stem cell proliferation and neuronal cell production. Activation of oncogenes involved in uncontrolledproliferation or tumorigenicity of stem cells is also discussed. It is proposed that a selective molecular manipulation targeting strategywill greatly benefit cell replacement therapy for PD by effectively promoting dopaminergic neuronal cell generation and reducing risk oftumorigenicity of in vivo stem cell applications. © 2011 Bentham Science Publishers.