The AAA-ATPase VPS4 regulates extracellular secretion and lysosomal targeting of α-synuclein.
The AAA-ATPase VPS4 regulates extracellular secretion and lysosomal targeting of α-synuclein.
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DOI：
10.1371/journal.pone.0029460
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Takeda A
中科院分区：
文献类型：
--
作者：
Hasegawa T;Konno M;Baba T;Sugeno N;Kikuchi A;Kobayashi M;Miura E;Tanaka N;Tamai K;Furukawa K;Arai H;Mori F;Wakabayashi K;Aoki M;Itoyama Y;Takeda A
许多神经退行性疾病都有一个共同的病理特征：由错误折叠的蛋白质组成的淀粉样原纤维的沉积。新的证据表明，这些蛋白质可能在细胞之间传播，并以类似朊病毒的方式促进神经退行性疾病的传播。在这里，我们证明α-突触核蛋白（αSYN）是帕金森病（PD）路易病理学的罪魁祸首，存在于内体区室中，并可检测地分泌到细胞外环境中。与朊病毒蛋白不同，细胞外αSYN主要在上清液中回收，而不是在神经元培养基和脑脊液中含有外泌体的沉淀中回收。令人惊讶的是，显性失活突变体液泡蛋白分选 4 (VPS4) 损害了多泡体 (MVB) 的生物发生，MVB 是一种衍生外泌体的细胞器，不仅干扰了 αSYN 的溶酶体靶向，而且促进了 αSYN 的分泌。通过循环内体调节因子 Rab11a 的功能破坏，VPS4 缺陷细胞中 αSYN 的过度分泌得到有效恢复。此外，PD 中的脑干和皮质路易体均被发现对 VPS4 具有免疫反应性。因此，VPS4，MVB 分选的主调节因子，可能作为 αSYN 溶酶体靶向或细胞外分泌的决定因素，从而有助于 PD 中路易病理学的细胞间传播。
Many neurodegenerative diseases share a common pathological feature: the deposition of amyloid-like fibrils composed of misfolded proteins. Emerging evidence suggests that these proteins may spread from cell-to-cell and encourage the propagation of neurodegeneration in a prion-like manner. Here, we demonstrated that α-synuclein (αSYN), a principal culprit for Lewy pathology in Parkinson's disease (PD), was present in endosomal compartments and detectably secreted into the extracellular milieu. Unlike prion protein, extracellular αSYN was mainly recovered in the supernatant fraction rather than in exosome-containing pellets from the neuronal culture medium and cerebrospinal fluid. Surprisingly, impaired biogenesis of multivesicular body (MVB), an organelle from which exosomes are derived, by dominant-negative mutant vacuolar protein sorting 4 (VPS4) not only interfered with lysosomal targeting of αSYN but facilitated αSYN secretion. The hypersecretion of αSYN in VPS4-defective cells was efficiently restored by the functional disruption of recycling endosome regulator Rab11a. Furthermore, both brainstem and cortical Lewy bodies in PD were found to be immunoreactive for VPS4. Thus, VPS4, a master regulator of MVB sorting, may serve as a determinant of lysosomal targeting or extracellular secretion of αSYN and thereby contribute to the intercellular propagation of Lewy pathology in PD.
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DOI：
10.1038/nrm2937
发表时间：
2010-08
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
34.7
作者：
Frost, Bess;Diamond, Marc I.
通讯作者：
Diamond, Marc I.
影响因子：
4.7
作者：
Furukawa, K;Matsuzaki-Kobayashi, M;Takeda, A
通讯作者：
Takeda, A
影响因子：
5.3
作者：
Emmanouilidou, Evangelia;Melachroinou, Katerina;Vekrellis, Kostas
通讯作者：
Vekrellis, Kostas
影响因子：
3.5
作者：
Hasegawa, T;Matsuzaki-Kobayashi, M;Itoyama, Y
通讯作者：
Itoyama, Y