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The C-terminal TDP-43 fragments have a high aggregation propensity and harm neurons by a dominant-negative mechanism.

PloS one | Jan 6, 2010

http://www.ncbi.nlm.nih.gov/pubmed/21209826

TAR DNA binding protein 43 KD (TDP-43) is an essential gene that regulates gene transcription, mRNA splicing and stability. In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two fatal neurodegenerative diseases, TDP-43 is fragmented, generating multiple fragments that include the C-terminal fragment of ∼25 KD. The role of these fragments in the pathogenesis of ALS and FTD is not clear. Here we investigated the aggregation propensity in various polypeptide regions of TDP-43 in mammalian cells and the effect of these fragments on cultured neurons. By expressing the full length and various TDP-43 fragments in motor neuron-derived NSC-34 cells and primary neurons, we found that both N- and C-terminal fragments of TDP-43 are prone to aggregate and the C-terminal end of RRM2 region is required, though not sufficient, for aggregation. The aggregation of the TDP-43 fragments can drive co-aggregation with the full-length TDP-43, consequently reducing the nuclear TDP-43. In addition, the TDP-43 fragments can impair neurite growth during neuronal differentiation. Importantly, overexpression of the full-length TDP-43 rescues the neurite growth phenotype whereas knockdown of the endogenous TDP-43 reproduces this phenotype. These results suggest that TDP-43 fragments, particularly the pathologically relevant C-terminal fragments, can impair neuronal differentiation by dominant-negatively interfering with the function of the full length TDP-43, thus playing a role in pathogenesis in ALS and FTD.

Pubmed ID: 21209826 RIS Download

Mesh terms: Animals | Cell Differentiation | Cell Line, Tumor | Cloning, Molecular | DNA-Binding Proteins | Exons | Genes, Dominant | Genetic Vectors | Green Fluorescent Proteins | Humans | Neurons | Protein Structure, Tertiary | RNA Splicing | RNA, Messenger | Transfection

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Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS048145
  • Agency: NINDS NIH HHS, Id: R21 NS062230

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