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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.

http://www.ncbi.nlm.nih.gov/pubmed/20660618

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 RIS Download

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

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Mouse Genome Informatics (Data, Gene Annotation)

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