Dept. Biosciences, Università degli Studi di Milano, Milano, Italy.
Dept. of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milano, Italy.
Sci Rep. 2016 Sep 15;6:33289. doi: 10.1038/srep33289.
α-Synuclein is a presynaptic protein associated to Parkinson's disease, which is unstructured when free in the cytoplasm and adopts α helical conformation when bound to vesicles. After decades of intense studies, α-Synuclein physiology is still difficult to clear up due to its interaction with multiple partners and its involvement in a pletora of neuronal functions. Here, we looked at the remarkably neglected interplay between α-Synuclein and microtubules, which potentially impacts on synaptic functionality. In order to identify the mechanisms underlying these actions, we investigated the interaction between purified α-Synuclein and tubulin. We demonstrated that α-Synuclein binds to microtubules and tubulin α2β2 tetramer; the latter interaction inducing the formation of helical segment(s) in the α-Synuclein polypeptide. This structural change seems to enable α-Synuclein to promote microtubule nucleation and to enhance microtubule growth rate and catastrophe frequency, both in vitro and in cell. We also showed that Parkinson's disease-linked α-Synuclein variants do not undergo tubulin-induced folding and cause tubulin aggregation rather than polymerization. Our data enable us to propose α-Synuclein as a novel, foldable, microtubule-dynamase, which influences microtubule organisation through its binding to tubulin and its regulating effects on microtubule nucleation and dynamics.
α-突触核蛋白是一种与帕金森病相关的突触前蛋白，在细胞质中自由时无结构，与囊泡结合时采用α螺旋构象。经过几十年的深入研究，由于其与多种伴侣相互作用以及参与众多神经元功能，α-突触核蛋白的生理学仍然难以阐明。在这里，我们研究了α-突触核蛋白和微管之间被显著忽视的相互作用，这可能对突触功能产生影响。为了确定这些作用的机制，我们研究了纯化的α-突触核蛋白和微管蛋白之间的相互作用。我们证明α-突触核蛋白结合微管和微管蛋白α2β2四聚体；后者的相互作用诱导α-突触核蛋白多肽中形成螺旋片段。这种结构变化似乎使α-突触核蛋白能够促进微管的成核，并增强微管的生长速度和崩溃频率，无论是在体外还是在细胞中。我们还表明，帕金森病相关的α-突触核蛋白变体不会发生微管诱导的折叠，并导致微管聚集而不是聚合。我们的数据使我们能够提出α-突触核蛋白作为一种新的、可折叠的微管动力酶，通过与微管蛋白结合以及对微管成核和动力学的调节作用来影响微管组织。
