C9ORF72-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons.
C9ORF72-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons.
复制标题
DOI：
10.26508/lsa.202101276
复制
发表时间：
2022-09
影响因子：
4.4
通讯作者：
Azzouz, Mimoun
中科院分区：
文献类型：
--
作者：
Marchi, Paolo M.;Marrone, Lara;Brasseur, Laurent;Coens, Audrey;Webster, Christopher P.;Bousset, Luc;Destro, Marco;Smith, Emma F.;Walther, Christa G.;Alfred, Victor;Marroccella, Raffaele;Graves, Emily J.;Robinson, Darren;Shaw, Allan C.;Wan, Lai Mei;Grierson, Andrew J.;Ebbens, Stephen J.;De Vos, Kurt J.;Hautbergue, Guillaume M.;Ferraiuolo, Laura;Melki, Ronald;Azzouz, Mimoun
细胞外递送的多聚GA通过内吞依赖性途径内化到星形胶质细胞中，然后扩散到运动神经元，这意味着C9 ORF 72-ALS/FTD中的非细胞自主机制。二肽重复序列（DPR）蛋白是由C9 ORF 72基因中致病性GGGGCC重复序列扩增编码的易聚集多肽，是肌萎缩侧索硬化和额颞叶痴呆的最常见遗传原因。在这项研究中，我们专注于poly-GA DPRs在疾病传播中的作用。我们证明了重组poly-GA寡聚物可以在体外直接转化为固体样聚集体并形成特征性β-折叠原纤维。为了剖析细胞到细胞DPR传递的过程，我们密切关注在细胞培养基中施用后以其寡聚体或纤维化形式的聚-GA DPR的命运。我们观察到，聚-GA DPRs通过动力蛋白依赖性和非依赖性的内吞作用被摄取，最终会聚在溶酶体隔室并导致神经元中的轴突肿胀。然后，我们使用共培养系统来证明星形胶质细胞到运动神经元的DPR传播，表明星形胶质细胞可能在疾病发病机制中内化和释放异常肽。总的来说，我们的研究结果揭示了聚-GA细胞摄取和繁殖的机制，表明溶酶体损伤作为这些DPR物种的细胞致病性的潜在特征。
Extracellularly delivered poly-GAs are internalised into astrocytes via an endocytosis-dependent pathway and then spread to motor neurons, implying non-cell autonomous mechanisms in C9ORF72-ALS/FTD. Dipeptide repeat (DPR) proteins are aggregation-prone polypeptides encoded by the pathogenic GGGGCC repeat expansion in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. In this study, we focus on the role of poly-GA DPRs in disease spread. We demonstrate that recombinant poly-GA oligomers can directly convert into solid-like aggregates and form characteristic β-sheet fibrils in vitro. To dissect the process of cell-to-cell DPR transmission, we closely follow the fate of poly-GA DPRs in either their oligomeric or fibrillized form after administration in the cell culture medium. We observe that poly-GA DPRs are taken up via dynamin-dependent and -independent endocytosis, eventually converging at the lysosomal compartment and leading to axonal swellings in neurons. We then use a co-culture system to demonstrate astrocyte-to-motor neuron DPR propagation, showing that astrocytes may internalise and release aberrant peptides in disease pathogenesis. Overall, our results shed light on the mechanisms of poly-GA cellular uptake and propagation, suggesting lysosomal impairment as a possible feature underlying the cellular pathogenicity of these DPR species.
登录
查看更多内容
影响因子：
3.7
作者：
Fonin AV;Sulatskaya AI;Kuznetsova IM;Turoverov KK
通讯作者：
Turoverov KK
影响因子：
3.6
作者：
Cullen, Valerie;Lindfors, Maria;Ng, Juliana;Paetau, Anders;Swinton, Erika;Kolodziej, Piotr;Boston, Heather;Saftig, Paul;Woulfe, John;Feany, Mel B.;Myllykangas, Liisa;Schlossmacher, Michael G.;Tyynela, Jaana
通讯作者：
Tyynela, Jaana
影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
13.6
作者：
Fumagalli L;Young FL;Boeynaems S;De Decker M;Mehta AR;Swijsen A;Fazal R;Guo W;Moisse M;Beckers J;Dedeene L;Selvaraj BT;Vandoorne T;Madan V;van Blitterswijk M;Raitcheva D;McCampbell A;Poesen K;Gitler AD;Koch P;Vanden Berghe P;Thal DR;Verfaillie C;Chandran S;Van Den Bosch L;Bullock SL;Van Damme P
通讯作者：
Van Damme P
影响因子：
13.3
作者：
Aits, Sonja;Kricker, Jennifer;Jaattela, Marja
通讯作者：
Jaattela, Marja