α-Synuclein aggregates amplified from patient-derived Lewy bodies recapitulate Lewy body diseases in mice.
α-Synuclein aggregates amplified from patient-derived Lewy bodies recapitulate Lewy body diseases in mice.
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DOI：
10.1038/s41467-023-42705-5
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发表时间：
2023-10-28
影响因子：
16.6
通讯作者：
Lee, Virginia M. -Y.
中科院分区：
文献类型：
--
作者：
Uemura, Norihito;Marotta, Nicholas P.;Ara, Jahan;Meymand, Emily S.;Zhang, Bin;Kameda, Hiroshi;Koike, Masato;Luk, Kelvin C.;Trojanowski, John Q.;Lee, Virginia M. -Y.
从路易体病（LBD）脑中提取α-突触核蛋白（αSyn）聚集体已被广泛报道，但LB-αSyn的模板化纤维化往往不能传播其结构和功能特性。我们最近证明，与从头形成的人αSyn预形成原纤维（hPFF）相比，LB-αSyn （ampLB）扩增的聚集体在体外表现出不同的生物活性。在这里，我们比较了hPFF和ampLB在体内的生物学活性，包括播种活性、诱导病理潜伏期、病理分布、包涵形态和细胞类型偏好。将ampLB注射到仅表达人α - syn的小鼠（雄性Thy1:SNCA/ SNCA - / -小鼠）中，诱导的病理与LBD受试者相似，与hff注射诱导的病理不同，或随年龄自发发展。重要的是，αSyn在注射了amplb的Thy1:SNCA/ SNCA - / -小鼠中的聚集保持了原始LB-αSyn独特的生物学和构象特征。这些结果表明，注射amplb，而不是传统的pff注射或αSyn过表达，真实地模拟了LBD的关键方面。路易小体(LBs) α-Synuclein聚集体由于患病脑的可用性有限，尚未广泛用于研究。在这里，作者报告了一个用LB扩增方法概括LB疾病的小鼠模型。
Extraction of α-Synuclein (αSyn) aggregates from Lewy body disease (LBD) brains has been widely described yet templated fibrillization of LB-αSyn often fails to propagate its structural and functional properties. We recently demonstrated that aggregates amplified from LB-αSyn (ampLB) show distinct biological activities in vitro compared to human αSyn preformed fibrils (hPFF) formed de novo. Here we compare the in vivo biological activities of hPFF and ampLB regarding seeding activity, latency in inducing pathology, distribution of pathology, inclusion morphology, and cell-type preference. Injection of ampLB into mice expressing only human αSyn (male Thy1:SNCA/Snca–/– mice) induced pathologies similar to those of LBD subjects that were distinct from those induced by hPFF-injection or developing spontaneously with aging. Importantly, αSyn aggregates in ampLB-injected Thy1:SNCA/Snca–/– mice maintained the unique biological and conformational features of original LB-αSyn. These results indicate that ampLB-injection, rather than conventional PFF-injection or αSyn overexpression, faithfully models key aspects of LBD. α-Synuclein aggregates in Lewy bodies (LBs) have not been widely used for research due to the limited availability of diseased brains. Here, the authors report a mouse model that recapitulates LB diseases using the LB amplification method.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
DOI：
10.1073/pnas.1512876113
发表时间：
2016-02-16
影响因子：
11.1
作者：
Fares, Mohamed-Bilal;Maco, Bohumil;Lashuel, Hilal A.
通讯作者：
Lashuel, Hilal A.
影响因子：
82.9
作者：
Conway, KA;Harper, JD;Lansbury, PT
通讯作者：
Lansbury, PT
DOI：
10.1126/science.1227157
发表时间：
2012-11-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Luk KC;Kehm V;Carroll J;Zhang B;O'Brien P;Trojanowski JQ;Lee VM
通讯作者：
Lee VM
DOI：
10.1073/pnas.1514475112
发表时间：
2015-09-22
影响因子：
11.1
作者：
Prusiner, Stanley B.;Woerman, Amanda L.;Giles, Kurt
通讯作者：
Giles, Kurt