The Babraham Institute, Cambridge, UK.
Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s
College London, London, UK.
Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of
Cambridge, Cambridge, UK.
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.
Department of Neuroscience, Brown University, Providence, RI, USA.
John van Geest
Centre for Brain Repair, University of Cambridge, Cambridge, UK.
The Vollum Institute, Oregon Health & Science University, Portland, OR, USA.
Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Department of Neurology, UMass Medical School, Worcester, MA,
Molecular Medicine Research Group, Robarts Research Institute & Department of Physiology and Pharmacology, Schulich School of Medicine
& Dentistry, Western University, London, ON, Canada.
The Brain and Mind Institute, Western University, London, ON, Canada.
SBMS, University of
Edinburgh, Edinburgh, UK.
Department of Cognitive, Linguistic and Psychological Sciences, Brown University, Providence, RI, USA. Present address:
Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK.
Biosciences, Dementia Research Institute, Cardiff University, Cardiff, UK.
Centre for Neuroscience and Trauma, Blizard Institute, Barts and the London
School of Medicine and Dentistry, Queen Mary University of London, London, UK.
These authors contributed equally: Matthew A. White, Eosu Kim.
myotrophic lateral sclerosis (ALS) and frontotemporal
dementia (FTD) are destructive neurodegenerative diseases
that exist on a clinicopathological spectrum (ALS-FTD)
ALS is characterized by motor impairment and FTD by executive
dysfunction, language impairment and behavioral changes. Nearly
all cases of ALS, half of FTD cases, and most hereditary forms of
ALS and FTD are characterized by cytoplasmic mislocalization
and aggregation of TDP-43
. The identification of mutations in
the gene encoding TDP-43 (TARDBP) as a cause of ALS and FTD
confirmed that TDP-43 plays a mechanistic role in neurodegenera
. This role remains undefined.
TDP-43 is a conserved RNA-binding protein with critical roles
in splicing in the nervous system
. TDP-43 also demonstrates tight
autoregulation by binding to its transcript, triggering alternative
splicing of intron 7 in the TARDBP 3′ untranslated region (UTR)
and destruction of its mRNA
. Experimentally increasing and
decreasing TDP-43 levels both cause neuronal loss, but whether
human neurodegeneration is caused by a gain or loss of TDP-43
function remains unclear. Modeling of mutant TDP-43 in vivo has
relied on variable degrees of transgenic overexpression of TDP-43 to
replicate pathological changes seen in postmortem human tissues
However, TDP-43 transgenic mouse models have demonstrated
that TDP-43 aggregation is not necessary to cause neurodegenera
, and whether TDP-43 aggregation is causally linked to disease
onset is unclear.
A caveat of transgenic TDP-43 mouse models is that pheno
types may partly be artifacts of overexpression. Furthermore, the
cell-type-specific expression of single TDP-43 splice forms in trans
genic models using neuronal promoters and temporally triggered
expression of transgenes in adulthood do not reflect the ubiquitous
expression and alternative splicing of Tardbp, including that occur
ring during embryonic development
. To unravel the role of mutant
TDP-43 in the disease pathogenesis, we created a knock-in mouse
harboring only a human-equivalent point mutation in the endog
enous mouse Tardbp gene. This model replicates the human mutant
state as closely as possible, retaining the endogenous gene structure
TDP-43 gains function due to perturbed
autoregulation in a Tardbp knock-in mouse
model of ALS-FTD
Matthew A. White
, Eosu Kim
, Amanda Duffy
, Robert Adalbert
, Benjamin U. Phillips
Owen M. Peters
, Jodie Stephenson
, Sujeong Yang
, Francesca Massenzio
, Ziqiang Lin
, Anne Segonds-Pichon
, Jake Metterville
, Lisa M. Saksida
, Richard Mead
Richard R Ribchester
, Youssef Barhomi
, Thomas Serre
, Michael P. Coleman
, Justin R. Fallon
Timothy J. Bussey
, Robert H. Brown Jr
and Jemeen Sreedharan
Amyotrophic lateral sclerosis–frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum character-
ized 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-43
mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneu-
rons. 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.
Corrected: Publisher Correction
NATURE NEUROSCIENCE | VOL 21 | APRIL 2018 | 552–563 | www.nature.com/natureneuroscience
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