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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.

Pubmed ID: 20133711


  • Wils H
  • Kleinberger G
  • Janssens J
  • Pereson S
  • Joris G
  • Cuijt I
  • Smits V
  • Ceuterick-de Groote C
  • Van Broeckhoven C
  • Kumar-Singh S


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 23, 2010

Associated Grants


Mesh Terms

  • Amyotrophic Lateral Sclerosis
  • Animals
  • DNA-Binding Proteins
  • Frontotemporal Lobar Degeneration
  • Humans
  • Inclusion Bodies
  • Mice
  • Mice, Transgenic
  • Muscle Spasticity
  • Mutation, Missense
  • Paralysis