Abstract
BackgroundTAR DNA-binding protein 43 (TDP-43) is a protein that is involved in the pathology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). In patients with these neurodegenerative diseases, TDP-43 does not remain in its normal nuclear location, but instead forms insoluble aggregates in both the nucleus and cytoplasm of affected neurons.ResultsWe used high density peptide array analysis to identify regions in TDP-43 that are bound by TDP-43 itself and designed candidate peptides that might be able to reduce TDP-43 aggregation. We found that two of the synthetic peptides identified with this approach could effectively inhibit the formation of TDP-43 protein aggregates in a concentration-dependent manner in HeLa cells in which a mutated human TDP-43 gene was overexpressed. However, despite reducing aggregation, these peptides did not reduce or prevent cell death. Similar results were observed in HeLa cells treated with arsenite. Again we found reduced aggregation, in this case of wild type TDP-43, but no difference in cell death.ConclusionsOur results suggest that TDP-43 aggregation is associated with the cell death process rather than being a direct cause.
Highlights
TAR DNA-binding protein 43 (TDP-43) is a protein that is involved in the pathology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD)
TDP-43 protein binds with selected TDP-43 derived peptides on the membrane The protein array described in the Methods section was used to identify candidate binding regions at which TDP43 might interact with itself
Five separate and robust binding regions were found on the TDP-43 peptide array after incubating the membrane with recombinant TDP-43 protein followed by visualization of an antibody against TDP-43 (Figure 1)
Summary
TAR DNA-binding protein 43 (TDP-43) is a protein that is involved in the pathology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). In patients with these neurodegenerative diseases, TDP-43 does not remain in its normal nuclear location, but instead forms insoluble aggregates in both the nucleus and cytoplasm of affected neurons. TDP-43 is a 414 amino acid protein encoded by the TARDBP gene on chromosome 1 It was originally identified as a transcriptional repressor of the human immunodeficiency virus type 1 (HIV-1) gene [3,4] and the mammalian gene SP-10 [5]. TDP-43 normally is found in the nucleus where it regulates RNA splicing, mRNA stability and microRNA processing [6,7,8,9], but TDP-43 in
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