Schneider, B. L.Seehus, C. R.Capowski, E. E.Aebischer, P.Zhang, S. C.Svendsen, C. N.2008-08-272008-08-272008-08-27200710.1093/hmg/ddm008https://infoscience.epfl.ch/handle/20.500.14299/27562WOS:000246122200008Missense mutations and extra copies of the alpha-Synuclein gene result in Parkinson disease (PD). Human stem and progenitor cells can be expanded from embryonic tissues and provide a source of non-transformed neural cells to explore the effects of these pathogenic mutations specifically in human nervous tissue. We over-expressed the wild type, A53T and A30P forms of alpha-synuclein in expanded populations of progenitors derived from the human fetal cortex. The protein localized in the nucleus and around microvesicles. Only the A53T form was acutely toxic, suggesting a unique vulnerability of these progenitors to this mutation. Interestingly, constitutive over-expression of wild-type alpha-synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of alpha-synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, alpha-synuclein and its mutations were also over-expressed in terminally differentiating neuroectodermal cultures derived from human embryonic stem cells (hESC). Alpha-synuclein induced acute cytotoxicity and reduced the number of neurons expressing either tyrosine hydroxylase or gamma-aminobutyric acid over time. Consistent with the selective vulnerability of ventral midbrain dopaminergic neurons, alpha-synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that alpha-synuclein over-expressed in human neural embryonic cells results in patterns of degeneration that in some cases match features of Parkinson Disease. Thus, neural cells derived from hESC provide a useful model system to understand the development of alpha-synuclein-related pathologies and allow therapeutic drug screening.Cell Death*Cell DifferentiationCell Nucleus/metabolismCell ProliferationCytoplasm/metabolismEmbryonic Stem Cells/cytology/*metabolismFetal Stem Cells/metabolismFibroblast Growth Factor 8/metabolismHedgehog Proteins/metabolismHumansMaleMutationNeuroglia/cytology/metabolismNeurons/cytology/*metabolismParkinson Disease/metabolismalpha-Synuclein/*geneticstext::journal::journal article::research article