Journal Article

Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation

Bernard L. Schneider, Corey R. Seehus, Elizabeth E. Capowski, Patrick Aebischer, Su-Chun Zhang and Clive N. Svendsen

in Human Molecular Genetics

Volume 16, issue 6, pages 651-666
Published in print March 2007 | ISSN: 0964-6906
Published online February 2007 | e-ISSN: 1460-2083 | DOI:
Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation

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Missense mutations and extra copies of the α-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 α-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 α-synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of α-synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, α-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, α-synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that α-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 α-synuclein-related pathologies and allow therapeutic drug screening.

Journal Article.  9864 words.  Illustrated.

Subjects: Genetics and Genomics

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