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TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD
 Authors and Affiliations  Authors and Affiliations
Matthew A. White1,2,14, Eosu Kim3,4, Amanda Duffy5, Robert Adalbert6, Benjamin U. Phillips3, Owen M. Peters7,15, Jodie Stephenson8,16, Sujeong Yang6, Francesca Massenzio1,2, Ziqiang Lin1,2, Simon Andrews1, Anne Segonds-Pichon1, Jake Metterville9, Lisa M. Saksida3,10,11, Richard Mead8, Richard R Ribchester12, Youssef Barhomi13, Thomas Serre13, Michael P. Coleman1,6, Justin Fallon5, Timothy J. Bussey3,10,11, Robert H. Brown Jr9 and Jemeen Sreedharan1,2,14*
1The Babraham Institute, Cambridge, UK. 2Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK. 3Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. 4Department of Psychiatry, Institute of Behavioral Science in Medicine, Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea. 5Department of Neuroscience, Brown University, Providence, RI, USA. 6John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK. 7The Vollum Institute, Oregon Health & Science University, Portland, OR, USA. 8Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK. 9Department of Neurology, UMass Medical School, Worcester, MA, USA. 10Molecular Medicine Research Group, Robarts Research Institute & Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada. 11The Brain and Mind Institute, Western University, London, ON, Canada. 12SBMS, University of Edinburgh, Edinburgh, UK. 13Department of Cognitive, Linguistic and Psychological Sciences, Brown University, Providence, RI, USA. Present address: 14Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK. 15School of Biosciences, Dementia Research Institute, Cardiff University, Cardiff, UK. 16Centre for Neuroscience and Trauma, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 17These authors contributed equally: Matthew A. White and Eosu Kim
*Correspondence to Jemeen Sreedharan
Abstract Amyotrophic lateral sclerosis?frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterized by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here we have created a TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed, leading to a gain of TDP-43 function and altered splicing of Mapt, another pivotal dementia-associated gene. Furthermore, a new approach to stratify transcriptomic data by phenotype in differentially affected mutant mice revealed 471 changes linked with improved behavior. These changes included downregulation of two known modifiers of neurodegeneration, Atxn2 and Arid4a, and upregulation of myelination and translation genes. With one base change in murine Tardbp, this study identifies TDP-43 misregulation as a pathogenic mechanism that may underpin ALS-FTD and exploits phenotypic heterogeneity to yield candidate suppressors of neurodegenerative disease.
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