The Truncated C-terminal RNA Recognition Motif of TDP-43 Protein Plays a Key Role in Forming Proteinaceous Aggregates
TDP-43 is the major pathological protein identified in the cellular inclusions in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The pathogenic forms of TDP-43 are processed C-terminal fragments containing a truncated RNA-recognition motif (RRM2) and a glycine-rich region. Alth...
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Veröffentlicht in: | The Journal of biological chemistry 2013-03, Vol.288 (13), p.9049-9057 |
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Zusammenfassung: | TDP-43 is the major pathological protein identified in the cellular inclusions in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The pathogenic forms of TDP-43 are processed C-terminal fragments containing a truncated RNA-recognition motif (RRM2) and a glycine-rich region. Although extensive studies have focused on this protein, it remains unclear how the dimeric full-length TDP-43 is folded and assembled and how the processed C-terminal fragments are misfolded and aggregated. Here, using size-exclusion chromatography, pulldown assays, and small angle x-ray scattering, we show that the C-terminal-deleted TDP-43 without the glycine-rich tail is sufficient to form a head-to-head homodimer primarily via its N-terminal domain. The truncated RRM2, as well as two β-strands within the RRM2, form fibrils in vitro with a similar amyloid-negative staining property to those of TDP-43 pathogenic fibrils in diseases. In addition to the glycine-rich region, the truncated RRM2, but not the intact RRM2, plays a key role in forming cytoplasmic inclusions in neuronal cells. Our data thus suggest that the process that disrupts the dimeric structure, such as the proteolytic cleavage of TDP-43 within the RRM2 that removes the N-terminal dimerization domain, may produce unassembled truncated RRM2 fragments with abnormally exposed β-strands, which can oligomerize into high-order inclusions.
Background: TDP-43 forms aggregates in various neurodegenerative disorders.
Results: The C-terminal-truncated RRM2 of TDP-43 forms non-amyloid fibrils in vitro and plays a dominant role in forming inclusions in vivo.
Conclusion: The proteolytic cleavage of TDP-43 that removes the N-terminal dimerization domain may produce unassembled truncated RRM2 fragments for aggregation.
Significance: This result provides a new direction for the prevention and treatment of TDP-43-associated diseases. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M112.438564 |