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Nat Neurosci. 2018 Apr;21(4):552-563. doi: 10.1038/s41593-018-0113-5. Epub 2018 Mar 19.

TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD.

Author information

1
The Babraham Institute, Cambridge, UK.
2
Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
3
Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
4
Department 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.
5
Department of Neuroscience, Brown University, Providence, RI, USA.
6
John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
7
The Vollum Institute, Oregon Health & Science University, Portland, OR, USA.
8
School of Biosciences, Dementia Research Institute, Cardiff University, Cardiff, UK.
9
Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
10
Centre for Neuroscience and Trauma, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
11
Department of Neurology, UMass Medical School, Worcester, MA, USA.
12
Molecular Medicine Research Group, Robarts Research Institute & Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.
13
The Brain and Mind Institute, Western University, London, ON, Canada.
14
SBMS, University of Edinburgh, Edinburgh, UK.
15
Department of Cognitive, Linguistic and Psychological Sciences, Brown University, Providence, RI, USA.
16
The Babraham Institute, Cambridge, UK. jemeen.sreedharan@kcl.ac.uk.
17
Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. jemeen.sreedharan@kcl.ac.uk.

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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