Biomedical Imaging GroupSTI
English only   BIG > Publications > alpha-Synuclein

 Home Page
 News & Events
 Tutorials and Reviews
 Download Algorithms

 All BibTeX References

Phosphorylation Does Not Prompt, Nor Prevent, the Formation of α-Synuclein Toxic Species in a Rat Model of Parkinson's Disease

S.A. da Silveira, B.L. Schneider, C. Cifuentes-Diaz, D. Sage, T. Abbas-Terki, T. Iwatsubo, M. Unser, P. Aebischer

Human Molecular Genetics, vol. 18, no. 5, pp. 872-887, March 1, 2009.

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 alphasynuclein 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.

AUTHOR="da Silveira, S.A. and Schneider, B.L. and Cifuentes-Diaz, C. and
        Sage, D. and Abbas-Terki, T. and Iwatsubo, T. and Unser, M. and
        Aebischer, P.",
TITLE="Phosphorylation Does Not Prompt, Nor Prevent, the Formation of
        $\alpha$-Synuclein Toxic Species in a Rat Model of {P}arkinson's
JOURNAL="Human Molecular Genetics",
month="March 1,",

© 2009 Oxford University Press. Personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution to servers or lists, or to reuse any copyrighted component of this work in other works must be obtained from Oxford University Press.
This material is presented to ensure timely dissemination of scholarly and technical work. Copyright and all rights therein are retained by authors or by other copyright holders. All persons copying this information are expected to adhere to the terms and constraints invoked by each author's copyright. In most cases, these works may not be reposted without the explicit permission of the copyright holder.