Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17004-9. doi: 10.1073/pnas.1109356108. Epub 2011 Sep 27.
α-Synuclein is an abundant brain protein that binds to lipid membranes and is involved in the recycling of presynaptic vesicles. In Parkinson disease, α-synuclein accumulates in intraneuronal inclusions often containing ubiquitin chains. Here we show that the ubiquitin ligase Nedd4, which functions in the endosomal-lysosomal pathway, robustly ubiquitinates α-synuclein, unlike ligases previously implicated in its degradation. Purified Nedd4 recognizes the carboxyl terminus of α-synuclein (residues 120-133) and attaches K63-linked ubiquitin chains. In human cells, Nedd4 overexpression enhances α-synuclein ubiquitination and clearance by a lysosomal process requiring components of the endosomal-sorting complex required for transport. Conversely, Nedd4 down-regulation increases α-synuclein content. In yeast, disruption of the Nedd4 ortholog Rsp5p decreases α-synuclein degradation and enhances inclusion formation and α-synuclein toxicity. In human brains, Nedd4 is present in pigmented neurons and is expressed especially strongly in neurons containing Lewy bodies. Thus, ubiquitination by Nedd4 targets α-synuclein to the endosomal-lysosomal pathway and, by reducing α-synuclein content, may help protect against the pathogenesis of Parkinson disease and other α-synucleinopathies.
α-突触核蛋白是一种丰富的脑蛋白，它与脂膜结合，并参与突触小泡的再循环。在帕金森病中，α-突触核蛋白在含有泛素链的神经元内包涵体中积累。在这里，我们表明，在溶酶体途径中起作用的泛素连接酶 Nedd4 强烈泛素化 α-突触核蛋白，与先前涉及其降解的连接酶不同。纯化的 Nedd4 识别 α-突触核蛋白的羧基末端（残基 120-133）并附着 K63 连接的泛素链。在人类细胞中，Nedd4 的过表达增强了溶酶体过程中的 α-突触核蛋白泛素化和清除作用，该过程需要运输所需的内体分选复合物的成分。相反，Nedd4 的下调增加了 α-突触核蛋白的含量。在酵母中，破坏 Nedd4 同源物 Rsp5p 会降低 α-突触核蛋白的降解并增强包涵体的形成和 α-突触核蛋白的毒性。在人类大脑中，Nedd4 存在于色素神经元中，在含有路易体的神经元中表达尤为强烈。因此，Nedd4 的泛素化将 α-突触核蛋白靶向内体-溶酶体途径，并通过降低 α-突触核蛋白的含量，可能有助于预防帕金森病和其他 α-突触核蛋白病的发病机制。
