Rodent models of TDP-43 proteinopathy: Investigating the mechanisms of TDP-43-mediated neurodegeneration

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47 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 and frontotemporal lobar degeneration with ubiquitin-positive inclusions, much effort has been directed towards ascertaining how TDP-43 contributes to the pathogenesis of disease. As with other protein misfolding disorders, TDP-43-mediated neuronal death is likely caused by both a toxic gain and loss of TDP-43 function. Indeed, the presence of cytoplasmic TDP-43 inclusions is associated with loss of nuclear TDP-43. Moreover, post-translational modifications of TDP-43, including phosphorylation, ubiquitination, and cleavage into C-terminal fragments, may bestow toxic properties upon TDP-43 and cause TDP-43 dysfunction. However, the exact neurotoxic TDP-43 species remain unclear, as do the mechanism(s) by which they cause neurotoxicity. Additionally, given our incomplete understanding of the roles of TDP-43, both in the nucleus and the cytoplasm, it is difficult to truly appreciate the detrimental consequences of aberrant TDP-43 function. The development of TDP-43 transgenic animal models is expected to narrow these gaps in our knowledge. The aim of this review is to highlight the key findings emerging from TDP-43 transgenic animal models and the insight they provide into the mechanisms driving TDP-43-mediated neurodegeneration.

Original languageEnglish (US)
Pages (from-to)486-499
Number of pages14
JournalJournal of Molecular Neuroscience
Volume45
Issue number3
DOIs
StatePublished - Nov 2011

Keywords

  • Amyotrophic lateral sclerosis
  • Frontotemporal lobar degeneration
  • Neurodegeneration
  • TDP-43
  • Transgenic animal models

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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