Phosphorylation does not prompt, nor prevent, the formation of -synuclein toxic species in a rat model of Parkinson's disease
Identifieur interne : 000860 ( Main/Exploration ); précédent : 000859; suivant : 000861Phosphorylation does not prompt, nor prevent, the formation of -synuclein toxic species in a rat model of Parkinson's disease
Auteurs : Samareh Azeredo Da Silveira ; Bernard L. Schneider ; Carmen Cifuentes-Diaz [France] ; Daniel Sage ; Toufik Abbas-Terki ; Takeshi Iwatsubo ; Michal Unser [France] ; Patrick Aebischer [Suisse]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2009-03-01.
Abstract
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.
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DOI: 10.1093/hmg/ddn417
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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.</div></front></TEI><affiliations><list><country><li>France</li><li>Suisse</li></country><region><li>Île-de-France</li></region><settlement><li>Paris</li></settlement></list><tree><noCountry><name sortKey="Abbas Terki, Toufik" sort="Abbas Terki, Toufik" uniqKey="Abbas Terki T" first="Toufik" last="Abbas-Terki">Toufik Abbas-Terki</name><name sortKey="Azeredo Da Silveira, Samareh" sort="Azeredo Da Silveira, Samareh" uniqKey="Azeredo Da Silveira S" first="Samareh" last="Azeredo Da Silveira">Samareh Azeredo Da Silveira</name><name sortKey="Iwatsubo, Takeshi" sort="Iwatsubo, Takeshi" uniqKey="Iwatsubo T" first="Takeshi" last="Iwatsubo">Takeshi Iwatsubo</name><name sortKey="Sage, Daniel" sort="Sage, Daniel" uniqKey="Sage D" first="Daniel" last="Sage">Daniel Sage</name><name sortKey="Schneider, Bernard L" sort="Schneider, Bernard L" uniqKey="Schneider B" first="Bernard L." last="Schneider">Bernard L. 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