Azeredo da Silveira Samareh, Schneider Bernard L, Cifuentes-Diaz Carmen, Sage Daniel, Abbas-Terki Toufik, Iwatsubo Takeshi, Unser Michaël, Aebischer Patrick
Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Hum Mol Genet. 2009 Mar 1;18(5):872-87. doi: 10.1093/hmg/ddn417. Epub 2008 Dec 12.
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.
磷酸化与多种神经退行性疾病有关。特别是，在患有突触核蛋白病的患者的聚集体中，α-突触核蛋白被广泛磷酸化。然而，这种修饰在导致α-突触核蛋白转化为聚集的有毒物种的事件中所占的比例尚待阐明。我们通过rAAV2/6介导的α-突触核蛋白表达开发的大鼠模型表明神经退行性变与小丝状α-突触核蛋白聚集体的形成之间存在相关性。一种阻止磷酸化的突变（S129A）显著增加了α-突触核蛋白的毒性，并导致富含β-折叠、蛋白酶K抗性聚集体的形成增加、对细胞内膜的亲和力增加、神经丝网络紊乱以及α-突触核蛋白核定位增强。模拟磷酸化的突变（S129D）的表达不会导致多巴胺能细胞丢失。然而，形成的聚集体数量更少但更大，并且在表达α-突触核蛋白磷酸化模拟形式的大鼠中也激活了凋亡信号。这些观察结果强烈表明磷酸化在细胞毒性预包涵体聚集体的积累中不发挥积极作用。出乎意料的是，该研究还表明α-突触核蛋白磷酸化模拟形式的组成型表达并不能防止神经退行性变。研究了丝氨酸129位点的磷酸化在帕金森病早期阶段的作用，这为专注于调节激酶/磷酸酶活性以控制α-突触核蛋白毒性的治疗方法带来了新的视角。
