Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation
Missense 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.
Keywords: Cell Death ; *Cell Differentiation ; Cell Nucleus/metabolism ; Cell Proliferation ; Cytoplasm/metabolism ; Embryonic Stem Cells/cytology/*metabolism ; Fetal Stem Cells/metabolism ; Fibroblast Growth Factor 8/metabolism ; Hedgehog Proteins/metabolism ; Humans ; Male ; Mutation ; Neuroglia/cytology/metabolism ; Neurons/cytology/*metabolism ; Parkinson Disease/metabolism ; alpha-Synuclein/*genetics
Waisman Center and Department of Anatomy, University of Wisconsin, Madison, WI 53705, USA.
Record created on 2008-08-27, modified on 2016-08-08