Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation
Identifieur interne : 000E95 ( Main/Exploration ); précédent : 000E94; suivant : 000E96Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation
Auteurs : Bernard L. Schneider ; Corey R. Seehus ; Elizabeth E. Capowski ; Patrick Aebischer ; Su-Chun Zhang ; Clive N. Svendsen [États-Unis]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2007-03-15.
Abstract
Missense mutations and extra copies of the -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 -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 -synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of -synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, -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, -synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that -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 -synuclein-related pathologies and allow therapeutic drug screening.
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DOI: 10.1093/hmg/ddm008
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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 -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 -synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of -synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, -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, -synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that -synuclein over-expressed in human neural embryonic cells results in patterns of degeneration that in some cases match features of Parkinson Disease. 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