TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration.
Neuronal cytoplasmic and intranuclear aggregates of RNA-binding protein TDP-43 are a hallmark feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). ALS and FTLD show a considerable clinical and pathological overlap and occur as both familial and sporadic forms. Though missense mutations in TDP-43 cause rare forms of familial ALS, it is not yet known whether this is due to loss of TDP-43 function or gain of aberrant function. Moreover, the role of wild-type (WT) TDP-43, associated with the majority of familial and sporadic ALS/FTLD patients, is also currently unknown. Generating homozygous and hemizygous WT human TDP-43 transgenic mouse lines, we show here a dose-dependent degeneration of cortical and spinal motor neurons and development of spastic quadriplegia reminiscent of ALS. A dose-dependent degeneration of nonmotor cortical and subcortical neurons characteristic of FTLD was also observed. Neurons in the affected spinal cord and brain regions showed accumulation of TDP-43 nuclear and cytoplasmic aggregates that were both ubiquitinated and phosphorylated as observed in ALS/FTLD patients. Moreover, the characteristic approximately 25-kDa C-terminal fragments (CTFs) were also recovered from nuclear fractions and correlated with disease development and progression in WT TDP-43 mice. These findings suggest that approximately 25-kDa TDP-43 CTFs are noxious to neurons by a gain of aberrant nuclear function.
Wils
Hans
H
Department of Molecular Genetics, VIB, B-2610 Antwerpen, Belgium.
Kleinberger
Gernot
G
Janssens
Jonathan
J
Pereson
Sandra
S
Joris
Geert
G
Cuijt
Ivy
I
Smits
Veerle
V
Ceuterick-de Groote
Chantal
C
Van Broeckhoven
Christine
C
Kumar-Singh
Samir
S
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009128:Muscle Spasticity / Q000235:genetics / Q000473:pathology; D020125:Mutation, Missense; D010243:Paralysis / Q000235:genetics* / Q000473:pathology
D004268:DNA-Binding Proteins