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Human Molecular Genetics Advance Access published online on February 19, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm008
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Bernard L. Schneider1,2, Corey R. Seehus1, Elizabeth E. Capowski1, Patrick Aebischer2, Su-Chun Zhang1 and Clive N. Svendsen1,*

1 Waisman Center and Department of Anatomy, University of Wisconsin, Madison, USA 2 Brain & Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland

* Corresponding author : Clive N. Svendsen The Waisman Center, 1500 Highland Avenue, Madison, WI 53705 Tel: 608-265 8668 Fax: 608-263 5267 email: svendsen{at}waisman.wisc.edu

Received December 4, 2006; Revised January 30, 2007; Accepted January 30, 2007

Missense mutations and extra copies of the {alpha}-Synuclein gene result in Parkinson disease. 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 the 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 Parkinson disease, such as dopaminergic neurons, {alpha}-synuclein and its mutations were also over-expressed in terminally differentiating neuroectodermal cultures derived from human embryonic stem cells. 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 the disease features. Thus, neural cells derived from human embryonic stem cells provide a useful model system to understand the development of {alpha}-synuclein-related pathologies and allow therapeutic drug screening.


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