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 dosedependent degeneration of cortical and spinal motor neurons and development of spastic quadriplegia reminiscent of ALS. A dosedependent 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 ≈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 ≈25-kDa TDP-43 CTFs are noxious to neurons by a gain of aberrant nuclear function.A myotrophic lateral sclerosis (ALS) is one of the most common progressive neuromuscular diseases worldwide and is characterized by degeneration of cortical motor neurons, the motor nuclei of the brainstem, and the anterior horn cells of the spinal cord. Dysfunction and death of these neurons lead to muscle weakness, atrophy, and spasticity (1). Frontotemporal lobar degeneration (FTLD) is the second most common form of cortical dementia in the presenium, accounting for ≈20% of dementia patients in this age group (2). Both ALS and FTLD patients are characterized by ubiquitinated neuronal cytoplasmic and intranuclear inclusions (NCIs and NIIs) in affected brain regions (2). Approximately 20% of patients with ALS show frontal lobe dysfunction that overlaps with the pathology of FTLD, suggesting that FTLD and ALS are part of the same disease spectrum (3).The recent identification of the TAR DNA-binding protein-43 (TDP-43) as a major protein constituent of NCIs and NIIs in ALS and FTLD (FTLD-U or FTLD-TDP) patients has offered a molecular link between these two disorders (4, 5). TDP-43 is a 414-amino acid protein with two highly conserved RNA recognition motifs (RRM1 and RRM2), a nuclear localization signal (NLS) at the protein N-terminus, and a glycine-rich region mediating protein-protein interactions at the C-terminus (6-9). Pathological TDP-43 is abnormally ubiquitinated, hyperphosphorylated, and N-terminally cleaved to generate CTFs (4, 5).Missense mutations in the TDP-43 gene (TARDBP), mostly in the C-terminal glycine-rich region, have been identified in patients wi...

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