Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3.
Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3.
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DOI：
10.1126/science.aah3374
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发表时间：
2016-09-30
期刊：
影响因子：
--
通讯作者：
Dawson TM
中科院分区：
文献类型：
--
作者：
Mao X;Ou MT;Karuppagounder SS;Kam TI;Yin X;Xiong Y;Ge P;Umanah GE;Brahmachari S;Shin JH;Kang HC;Zhang J;Xu J;Chen R;Park H;Andrabi SA;Kang SU;Gonçalves RA;Liang Y;Zhang S;Qi C;Lam S;Keiler JA;Tyson J;Kim D;Panicker N;Yun SP;Workman CJ;Vignali DA;Dawson VL;Ko HS;Dawson TM
帕金森病 (PD) 是第二常见的神经退行性疾病，会导致运动缓慢、震颤、僵硬，并在 PD 后期导致认知障碍。病理学上，PD的特征是α-突触核蛋白在路易体和神经突中的积累。整个神经系统的神经元发生变性，黑质致密部的多巴胺神经元变性，导致PD的主要症状。在 PD 患者的大脑中，病理性 α-突触核蛋白似乎通过自我放大、传播和在邻近细胞和/或解剖学上相连的大脑区域之间以刻板和拓扑模式传播从一个细胞传播到另一个细胞。病理性 α-突触核蛋白的传播或传播正在成为 PD 发病机制的潜在重要驱动因素。负责病理性 α-突触核蛋白在细胞之间传递的潜在机制和分子实体尚不清楚，但病理性 α-突触核蛋白进入神经元被认为部分是通过活跃的网格蛋白依赖性内吞过程发生的。使用重组α-突触核蛋白预形成原纤维（PFF）作为模型系统来研究错误折叠的α-突触核蛋白从神经元到神经元的传递，我们通过链霉亲和素-AP（碱性磷酸酶）染色检测来筛选编码α-突触核蛋白-生物素PFF结合候选物的跨膜蛋白的文库。鉴定出三个结合 α-突触核蛋白 PFF 的阳性克隆，包括淋巴细胞激活基因 3 (LAG3)、神经毒素 1β 和淀粉样β前体样蛋白 1 (APLP1)。在这三种跨膜蛋白中，LAG3 对 α-突触核蛋白 PFF 的选择性比对 α-突触核蛋白单体的选择性最高。 α-突触核蛋白 PFF 以饱和方式与 LAG3 结合 (Kd = 77 nM)，而 α-突触核蛋白单体不与 LAG3 结合。免疫共沉淀还表明病理性 α-突触核蛋白 PFF 与 LAG3 特异性结合。 Tau PFF、β-淀粉样蛋白寡聚物和 β-淀粉样蛋白 PFF 不结合 LAG3，表明 LAG3 对 α-突触核蛋白 PFF 具有特异性。 α-突触核蛋白 PFF 的内化涉及 LAG3，因为 LAG3 的缺失会减少 α-突触核蛋白 PFF 的内吞作用。 LAG3 与内体 GTPases、Rab5 和 Rab7 共定位，并与病理性 α-突触核蛋白共内吞。 Neuron-to-neuron transmission of pathologic α-synuclein and the accompanying pathology and neurotoxicity is substantially attenuated by deletion of LAG3 or by LAG3 antibodies. LAG3的缺乏还大大延迟了α-突触核蛋白PFF诱导的多巴胺神经元的损失，以及体内生化和行为缺陷。我们发现病理性α-突触核蛋白的传递和毒性是通过与LAG3结合启动的，并且病理性α-突触核蛋白的神经元到神经元的传递涉及通过LAG3与神经元的结合而对外源性α-突触核蛋白PFF的内吞作用。 LAG3 或 LAG3 抗体的耗竭可显着减少病理性 α-突触核蛋白传播引起的病理。 LAG3 作为 α-突触核蛋白 PFF 结合蛋白的鉴定为开发旨在减缓 PD 和相关 α-突触核蛋白病进展的治疗方法提供了新的靶点。 LAG3 缺失或抗体会延迟 α-突触核蛋白 PFF 传输。与野生型神经元相比，LAG3 抗体或当 LAG3 被删除时，α-突触核蛋白 PFF 的结合和内吞作用显着减少，导致病理性 α-突触核蛋白传输和毒性延迟。吴一勋创作人物。
Parkinson’s disease (PD) is the second most common neurodegenerative disorder that leads to slowness of movement, tremor, rigidity and in the later stages of PD, cognitive impairment. Pathologically PD is characterized by the accumulation of α-synuclein in Lewy bodies and neurites. There is degeneration of neurons throughout the nervous system with the degeneration of dopamine neurons in the substantia nigra pars compacta leading to the major symptoms of PD. In the brains of PD patients, pathologic α-synuclein seems to spread from cell-to-cell via self-amplification, propagation, and transmission in a stereotypical and topographical pattern among neighboring cells and/or anatomically connected brain regions. The spread or transmission of pathologic α-synuclein is emerging as potentially important driver of PD pathogenesis. The underlying mechanisms and molecular entities responsible for the transmission of pathologic α-synuclein from cell-to-to cell are not known, but the entry of pathologic α-synuclein into neurons is thought to occur, in part through an active clathrin-dependent endocytic process. Using recombinant α-synuclein pre-formed fibrils (PFF) as a model system to study the transmission of misfolded α-synuclein from neuron to neuron, we screened a library encoding transmembrane proteins for α-synuclein-biotin PFF binding candidates via detection by streptavidin-AP (alkaline phosphatase) staining. Three positive clones were identified that bind α-synuclein PFF and include lymphocyte-activation gene 3 (LAG3), neurexin 1β and amyloid beta precursor-like protein 1 (APLP1). Of these three transmembrane proteins, LAG3 demonstrated the highest ratio of selectivity for α-synuclein PFF over the α-synuclein monomer. α-Synuclein PFF binds to LAG3 in a saturable manner (Kd = 77 nM), while the α-synuclein monomer does not bind to LAG3. Co-immunoprecipitation also suggests that pathological α-synuclein PFF specifically binds to LAG3. Tau PFF, β-amyloid oligomer and β-amyloid PFF do not bind LAG3 indicating that LAG3 is specific for α-synuclein PFF. The internalization of α-synuclein PFF involves LAG3 since deletion of LAG3 reduces the endocytosis of α-synuclein PFF. LAG3 colocalizes with the endosomal GTPases, Rab5 and Rab7 and co-endocytoses with pathologic α-synuclein. Neuron-to-neuron transmission of pathologic α-synuclein and the accompanying pathology and neurotoxicity is substantially attenuated by deletion of LAG3 or by LAG3 antibodies. The lack of LAG3 also substantially delayed α-synuclein PFF induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. We discovered that pathologic α-synuclein transmission and toxicity is initiated by binding to LAG3 and that neuron-to-neuron transmission of pathological α-synuclein involves the endocytosis of exogenous α-synuclein PFF by the engagement of LAG3 on neurons. Depletion of LAG3 or antibodies to LAG3 substantially reduce the pathology set in motion by the transmission of pathologic α-synuclein. The identification of LAG3 as an α-synuclein PFF binding protein provides a new target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies. LAG3 deletion or antibodies delays α-synuclein PFF transmission. Compared to wild-type neurons, binding and endocytosis of α-synuclein PFF is dramatically reduced with LAG3 antibodies or when LAG3 is deleted, resulting in delayed pathologic α-synuclein transmission and toxicity. I-Hsun Wu created figure.
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DOI：
10.1111/j.1600-0854.2008.00853.x
发表时间：
2009-02
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Ben Gedalya T;Loeb V;Israeli E;Altschuler Y;Selkoe DJ;Sharon R
通讯作者：
Sharon R
影响因子：
4
作者：
Angelova PR;Ludtmann MH;Horrocks MH;Negoda A;Cremades N;Klenerman D;Dobson CM;Wood NW;Pavlov EV;Gandhi S;Abramov AY
通讯作者：
Abramov AY
DOI：
10.1073/pnas.132197599
发表时间：
2002-06-25
影响因子：
11.1
作者：
Lee, MK;Stirling, W;Price, DL
通讯作者：
Price, DL
影响因子：
4.7
作者：
Hettiarachchi, Nishani T.;Parker, Andrew;Peers, Chris
通讯作者：
Peers, Chris
影响因子：
4.8
作者：
Guo, Jing L.;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.