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Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U.

TDP-43 is a multifunctional DNA/RNA-binding factor that has been implicated in the regulation of neuronal plasticity. TDP-43 has also been identified as the major constituent of the neuronal cytoplasmic inclusions (NCIs) that are characteristic of a range of neurodegenerative diseases, including the frontotemporal lobar degeneration with ubiquitin(+) inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). We have generated a FTLD-U mouse model (CaMKII-TDP-43 Tg) in which TDP-43 is transgenically overexpressed in the forebrain resulting in phenotypic characteristics mimicking those of FTLD-U. In particular, the transgenic (Tg) mice exhibit impaired learning/memory, progressive motor dysfunction, and hippocampal atrophy. The cognitive and motor impairments are accompanied by reduced levels of the neuronal regulators phospho-extracellular signal-regulated kinase and phosphorylated cAMP response element-binding protein and increased levels of gliosis in the brains of the Tg mice. Moreover, cells with TDP-43(+), ubiquitin(+) NCIs and TDP-43-deleted nuclei appear in the Tg mouse brains in an age-dependent manner. Our data provide direct evidence that increased levels of TDP-43 protein in the forebrain is sufficient to lead to the formation of TDP-43(+), ubiquitin(+) NCIs and neurodegeneration. This FTLD-U mouse model should be valuable for the mechanistic analysis of the role of TDP-43 in the pathogenesis of FTLD-U and for the design of effective therapeutic approaches of the disease.

Pubmed ID: 20660618

Authors

  • Tsai KJ
  • Yang CH
  • Fang YH
  • Cho KH
  • Chien WL
  • Wang WT
  • Wu TW
  • Lin CP
  • Fu WM
  • Shen CK

Journal

The Journal of experimental medicine

Publication Data

August 2, 2010

Associated Grants

None

Mesh Terms

  • Animals
  • Apoptosis
  • Atrophy
  • Brain
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Caspase 3
  • Cell Nucleus
  • Cerebral Cortex
  • Cognition Disorders
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Electrophysiological Phenomena
  • Extracellular Signal-Regulated MAP Kinases
  • Frontotemporal Lobar Degeneration
  • Gene Expression
  • Glutamate Decarboxylase
  • Hippocampus
  • Inclusion Bodies
  • Long-Term Potentiation
  • Mice
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Nerve Tissue Proteins
  • Neurons
  • Phosphorylation
  • Psychomotor Disorders
  • Reflex, Abnormal
  • Survival Rate
  • Ubiquitin
  • gamma-Aminobutyric Acid