Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 8, Pages 3858-3863Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0912417107
Keywords
protein aggregation; neurodegeneration; dementia; motor neuron disease; FTLD
Categories
Funding
- Medical Foundation Queen Elisabeth
- Foundation for Alzheimer Research (SAO/FRMA)
- Interuniversity Attraction Poles (IAP) [P6/43]
- Flemish Government
- Fund for Scientific Research-Flanders (FWO-V)
- Institute for the Promotion of Innovation Through Science and Technology in Flanders (IWT-V)
- University of Antwerp, Belgium
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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 approximate 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 approximate to 25-kDa TDP-43 CTFs are noxious to neurons by a gain of aberrant nuclear function.
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