Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases.
Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases.
复制标题
跨平台转录谱鉴定路易体病中常见和不同的分子病理学。
DOI：
10.1007/s00401-021-02343-x
复制
发表时间：
2021-09
影响因子：
12.7
通讯作者：
Ryten M
中科院分区：
文献类型：
--
作者：
Feleke R;Reynolds RH;Smith AM;Tilley B;Taliun SAG;Hardy J;Matthews PM;Gentleman S;Owen DR;Johnson MR;Srivastava PK;Ryten M
帕金森病（Parkinson's disease，PD）、帕金森病伴痴呆（Parkinson's disease with dementia，PDD）和路易体痴呆（Dementia with Lewy bodies，DLB）是三种临床、遗传和神经病理学上相互重叠的神经退行性疾病，统称为路易体病（Lewy body diseases，LBD）。PD发病机制涉及多种分子机制，但PDD和DLB的潜在机制在很大程度上仍然未知，这是一个知识空白，阻碍了疾病修饰疗法的发现。转录组学分析可以有助于解决这一差距，但在LBD中仍然有限。在这里，我们对来自28个个体的前扣带皮层样本应用配对的大块组织和单核RNA测序，包括健康对照、PD、PDD和DLB病例（每组n = 7），以转录组学分析LBD。使用这种方法，我们（i）发现了LBD中多种细胞类型的转录改变;（ii）发现了RNA剪接普遍失调的证据，特别是在PDD和DLB中;（iii）确定了潜在的剪接因子，与其他痴呆相关的神经退行性疾病有关，协调这种失调;和（iv）确定LBD之间的转录组学共性和区别，从而了解这三种临床疾病之间的关系。总之，这些发现对这些疾病的RNA靶向疗法的设计具有重要意义，并突出了PD初始发作和路易体痴呆后续发展之间的治疗机会的潜在分子“窗口”。在线版本包含补充材料，可通过10.1007/s 00401 -021-02343-x获得。
Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia. The online version contains supplementary material available at 10.1007/s00401-021-02343-x.
登录
查看更多内容
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
3.5
作者：
Bras J;Guerreiro R;Darwent L;Parkkinen L;Ansorge O;Escott-Price V;Hernandez DG;Nalls MA;Clark LN;Honig LS;Marder K;Van Der Flier WM;Lemstra A;Scheltens P;Rogaeva E;St George-Hyslop P;Londos E;Zetterberg H;Ortega-Cubero S;Pastor P;Ferman TJ;Graff-Radford NR;Ross OA;Barber I;Braae A;Brown K;Morgan K;Maetzler W;Berg D;Troakes C;Al-Sarraj S;Lashley T;Compta Y;Revesz T;Lees A;Cairns N;Halliday GM;Mann D;Pickering-Brown S;Dickson DW;Singleton A;Hardy J
通讯作者：
Hardy J
影响因子：
12.7
作者：
Bampton A;Gittings LM;Fratta P;Lashley T;Gatt A
通讯作者：
Gatt A
影响因子：
30.8
作者：
Chia R;Sabir MS;Bandres-Ciga S;Saez-Atienzar S;Reynolds RH;Gustavsson E;Walton RL;Ahmed S;Viollet C;Ding J;Makarious MB;Diez-Fairen M;Portley MK;Shah Z;Abramzon Y;Hernandez DG;Blauwendraat C;Stone DJ;Eicher J;Parkkinen L;Ansorge O;Clark L;Honig LS;Marder K;Lemstra A;St George-Hyslop P;Londos E;Morgan K;Lashley T;Warner TT;Jaunmuktane Z;Galasko D;Santana I;Tienari PJ;Myllykangas L;Oinas M;Cairns NJ;Morris JC;Halliday GM;Van Deerlin VM;Trojanowski JQ;Grassano M;Calvo A;Mora G;Canosa A;Floris G;Bohannan RC;Brett F;Gan-Or Z;Geiger JT;Moore A;May P;Krüger R;Goldstein DS;Lopez G;Tayebi N;Sidransky E;American Genome Center;Norcliffe-Kaufmann L;Palma JA;Kaufmann H;Shakkottai VG;Perkins M;Newell KL;Gasser T;Schulte C;Landi F;Salvi E;Cusi D;Masliah E;Kim RC;Caraway CA;Monuki ES;Brunetti M;Dawson TM;Rosenthal LS;Albert MS;Pletnikova O;Troncoso JC;Flanagan ME;Mao Q;Bigio EH;Rodríguez-Rodríguez E;Infante J;Lage C;González-Aramburu I;Sanchez-Juan P;Ghetti B;Keith J;Black SE;Masellis M;Rogaeva E;Duyckaerts C;Brice A;Lesage S;Xiromerisiou G;Barrett MJ;Tilley BS;Gentleman S;Logroscino G;Serrano GE;Beach TG;McKeith IG;Thomas AJ;Attems J;Morris CM;Palmer L;Love S;Troakes C;Al-Sarraj S;Hodges AK;Aarsland D;Klein G;Kaiser SM;Woltjer R;Pastor P;Bekris LM;Leverenz JB;Besser LM;Kuzma A;Renton AE;Goate A;Bennett DA;Scherzer CR;Morris HR;Ferrari R;Albani D;Pickering-Brown S;Faber K;Kukull WA;Morenas-Rodriguez E;Lleó A;Fortea J;Alcolea D;Clarimon J;Nalls MA;Ferrucci L;Resnick SM;Tanaka T;Foroud TM;Graff-Radford NR;Wszolek ZK;Ferman T;Boeve BF;Hardy JA;Topol EJ;Torkamani A;Singleton AB;Ryten M;Dickson DW;Chiò A;Ross OA;Gibbs JR;Dalgard CL;Traynor BJ;Scholz SW
通讯作者：
Scholz SW