Review: Transactive response DNA-binding protein 43 (TDP-43): Mechanisms of neurodegeneration

Research output: Contribution to journalReview article

52 Scopus citations

Abstract

Since the identification of phosphorylated and truncated transactive response DNA-binding protein 43 (TDP-43) as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions, and the discovery that mutations in the TDP-43 gene cause ALS, much effort has been directed towards establishing how TDP-43 contributes to the development of neurodegeneration. Although few in vivo models are presently available, findings thus far strongly support the involvement of abnormally modified TDP-43 in promoting TDP-43 aggregation and cellular mislocalization. Therefore, TDP-43-mediated neurotoxicity is likely to result from a combination of toxic gains of function conferred by TDP-43 inclusions as well as from the loss of normal TDP-43 function. Nonetheless, the exact neurotoxic TDP-43 species remain unclear, as do the mechanism(s) by which they cause neuronal death. Moreover, little is currently known about the roles of TDP-43, both in the nucleus and the cytoplasm, making it difficult to truly appreciate the detrimental consequences of aberrant TDP-43 function. This review will summarize what is currently understood regarding normal TDP-43 function and the involvement of TDP-43 in neurodegeneration, and will also highlight some of the many remaining questions in need of further investigation.

Original languageEnglish (US)
Pages (from-to)97-112
Number of pages16
JournalNeuropathology and Applied Neurobiology
Volume36
Issue number2
DOIs
StatePublished - Apr 2010

Keywords

  • Amyotrophic lateral sclerosis
  • Frontotemporal lobar degeneration with ubiquitin-positive inclusions
  • Inclusions
  • Neurodegeneration
  • Neurotoxicity
  • TDP-43

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Neurology
  • Clinical Neurology
  • Physiology (medical)

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