Esposito Alessandro, Dohm Christoph P, Kermer Pawel, Bähr Mathias, Wouters Fred S
Cell Biophysics Group at the European Neuroscience Institute-Göttingen, Waldweg, 33, 37073 Göttingen, Germany.
Neurobiol Dis. 2007 Jun;26(3):521-31. doi: 10.1016/j.nbd.2007.01.014. Epub 2007 Feb 16.
alpha-Synuclein is a primarily neuronal protein that is enriched at the pre-synapse. alpha-Synuclein and the microtubule binding protein tau have been implicated in neurodegenerative diseases. alpha-Synuclein is known to associate with phospholipid vesicles, regulates dopamine metabolism and exhibits chaperone activity, but its main role remains largely unknown. Furthermore, knowledge on its interactions and post-translational modifications is essential for a molecular understanding of alpha-synucleinopathies. We investigated alpha-synuclein mutations, causative for autosomal dominant forms of Parkinson's disease (A30P, A53T and E46K), and phosphorylation mutants at serine 129 (S129A and S129D) using fluorescently labelled alpha-synuclein, actin and tau. The investigation of colocalization, and protein-protein interactions by Förster resonance energy transfer and fluorescence lifetime imaging showed that alpha-synuclein associates with the actin cytoskeleton and interacts with tau. The A30P mutation and cytoskeletal destabilization decreased this interaction. Given the concurrent loss of membrane binding by this mutation, we propose a membrane-bound functional complex with tau that might involve the actin cytoskeleton.
α-突触核蛋白是一种主要存在于神经元中的蛋白质，在突触前富集。α-突触核蛋白和微管结合蛋白tau与神经退行性疾病有关。已知α-突触核蛋白与磷脂囊泡相关，调节多巴胺代谢并表现出伴侣活性，但其主要作用在很大程度上仍不清楚。此外，了解其相互作用和翻译后修饰对于从分子层面理解α-突触核蛋白病至关重要。我们使用荧光标记的α-突触核蛋白、肌动蛋白和tau，研究了导致常染色体显性帕金森病的α-突触核蛋白突变（A30P、A53T和E46K）以及丝氨酸129位点的磷酸化突变体（S129A和S129D）。通过Förster共振能量转移和荧光寿命成像对共定位以及蛋白质-蛋白质相互作用的研究表明，α-突触核蛋白与肌动蛋白细胞骨架相关并与tau相互作用。A30P突变和细胞骨架不稳定降低了这种相互作用。鉴于该突变同时导致膜结合丧失，我们提出一种与tau形成的膜结合功能复合物，可能涉及肌动蛋白细胞骨架。
