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Human Molecular Genetics Advance Access originally published online on December 12, 2008
Human Molecular Genetics 2009 18(5):872-887; doi:10.1093/hmg/ddn417
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Phosphorylation does not prompt, nor prevent, the formation of {alpha}-synuclein toxic species in a rat model of Parkinson's disease

Samareh Azeredo da Silveira1, Bernard L. Schneider1, Carmen Cifuentes-Diaz3,{dagger}, Daniel Sage2,{dagger}, Toufik Abbas-Terki1, Takeshi Iwatsubo4, Michaël Unser3 and Patrick Aebischer1,*

1 Brain Mind Institute 2 Biomedical Imaging Group, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland 3 INSERM, U839, Institut du Fer à Moulin, 75005 Paris, France 4 Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan

* To whom correspondence should be addressed. Tel: +41 216939505; Fax: +41 216939520; Email: patrick.aebischer{at}epfl.ch

Received September 23, 2008; Accepted December 7, 2008

Phosphorylation is involved in numerous neurodegenerative diseases. In particular, alpha-synuclein is extensively phosphorylated in aggregates in patients suffering from synucleinopathies. However, the share of this modification in the events that lead to the conversion of alpha-synuclein to aggregated toxic species needed to be clarified. The rat model that we developed through rAAV2/6-mediated expression of alpha-synuclein demonstrates a correlation between neurodegeneration and formation of small filamentous alpha-synuclein aggregates. A mutation preventing phosphorylation (S129A) significantly increases alpha-synuclein toxicity and leads to enhanced formation of beta-sheet-rich, proteinase K-resistant aggregates, increased affinity for intracellular membranes, a disarrayed network of neurofilaments and enhanced alpha-synuclein nuclear localization. The expression of a mutation mimicking phosphorylation (S129D) does not lead to dopaminergic cell loss. Nevertheless, fewer but larger aggregates are formed, and signals of apoptosis are also activated in rats expressing the phosphorylation-mimicking form of alpha-synuclein. These observations strongly suggest that phosphorylation does not play an active role in the accumulation of cytotoxic pre-inclusion aggregates. Unexpectedly, the study also demonstrates that constitutive expression of phosphorylation-mimicking forms of alpha-synuclein does not protect from neurodegeneration. The role of phosphorylation at Serine 129 in the early phase of Parkinson's disease is examined, which brings new perspective to therapeutic approaches focusing on the modulation of kinases/phosphatases activity to control alpha-synuclein toxicity.

{dagger} These authors contributed equally to this work.


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