Skip to Content

Dear Customer:

The current international situation is complex and volatile, and uncertain tariff policies may potentially impact our product prices. Given these uncertainties, we value your understanding regarding order-related matters.

If you decide to place an order during this period, we reserve the right to adjust the price based on the evolving situation. We understand that market changes may cause inconvenience. We will negotiate with you if there’s a significant price fluctuation due to tariff policy changes before the order’s actual delivery, and in such cases we may adjust or cancel the order as necessary.

Merck
CN
  • Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis.

Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis.

The EMBO journal (2018-05-17)
Pietro Fratta, Prasanth Sivakumar, Jack Humphrey, Kitty Lo, Thomas Ricketts, Hugo Oliveira, 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, Elizabeth Mc Fisher, Abraham Acevedo-Arozena
PMID29764981
ABSTRACT

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.