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Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis 下载免费PDF全文
Pietro Fratta Jose M Brito‐Armas Bernadett Kalmar Agnieszka Ule Yichao Yu Nicol Birsa Cristian Bodo Toby Collins Alexander E Conicella Alan Mejia Maza Alessandro Marrero‐Gagliardi Michelle Stewart Joffrey Mianne Silvia Corrochano Warren Emmett Gemma Codner Michael Groves Ryutaro Fukumura Yoichi Gondo Mark Lythgoe Erwin Pauws Emma Peskett Philip Stanier Lydia Teboul Martina Hallegger Andrea Calvo Adriano Chiò Adrian M Isaacs Nicolas L Fawzi Eric Wang David E Housman Francisco Baralle Linda Greensmith Emanuele Buratti Vincent Plagnol Abraham Acevedo‐Arozena 《The EMBO journal》2018,37(11)
TDP‐43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP‐43 function at physiological levels both in vitro and in vivo. Interestingly, we find that mutations within the C‐terminal domain of TDP‐43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP‐43 loss‐ and gain‐of‐function effects. TDP‐43 gain‐of‐function effects in these mice reveal a novel category of splicing events controlled by TDP‐43, referred to as “skiptic” exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain‐of‐function mutation in endogenous Tardbp causes an adult‐onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain‐of‐function and skiptic exons in ALS patient‐derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP‐43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages. 相似文献
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Zusammenfassung Die in den Milchflecken des Mäusemesenterium als Folge von Speicherungsversuchen mit Trypanblau auftretenden Gewebeleukozyten (Cricokaryocyten) zeigen keine grundsätzlichen Unterschiede gegenüber den im Knochenmark und im strömenden Blut anzutreffenden ringkernigen myeloischen Zellen. 相似文献
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Sandra Blanco Sabine Dietmann Joana V Flores Shobbir Hussain Claudia Kutter Peter Humphreys Margus Lukk Patrick Lombard Lucas Treps Martyna Popis Stefanie Kellner Sabine M Hölter Lillian Garrett Wolfgang Wurst Lore Becker Thomas Klopstock Helmut Fuchs Valerie Gailus‐Durner Martin Hrabĕ de Angelis Ragnhildur T Káradóttir Mark Helm Jernej Ule Joseph G Gleeson Duncan T Odom Michaela Frye 《The EMBO journal》2014,33(18):2020-2039
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A retained intron in the 3′‐UTR of Calm3 mRNA mediates its Staufen2‐ and activity‐dependent localization to neuronal dendrites 下载免费PDF全文