TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-02, Vol.107 (8), p.3858-3863
• Main Authors: Wils, Hans, Kleinberger, Gernot, Janssens, Jonathan, Pereson, Sandra, Joris, Geert, Cuijt, Ivy, Smits, Veerle, Ceuterick-de Groote, Chantal, Van Broeckhoven, Christine, Kumar-Singh, Samir
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Antibodies; Biological Sciences; Brain; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Frontotemporal lobar degeneration; Frontotemporal Lobar Degeneration - genetics; Frontotemporal Lobar Degeneration - metabolism; Frontotemporal Lobar Degeneration - pathology; Humans; Inclusion Bodies - genetics; Inclusion Bodies - metabolism; Mice; Mice, Transgenic; Muscle Spasticity - genetics; Muscle Spasticity - pathology; Mutation; Mutation, Missense; Nervous system diseases; Neurons; Neurosciences; Paralysis - genetics; Paralysis - pathology; Pathology; Proteins; Ribonucleic acid; RNA; Rodents; Spinal cord; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0912417107

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 [almost equal to]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 [almost equal to]25-kDa TDP-43 CTFs are noxious to neurons by a gain of aberrant nuclear function.