TDP-43 aggregation in neurodegeneration: Are stress granules the key?

Colleen M. Dewey, Basar Cenik, Chantelle F. Sephton, Brett A. Johnson, Joachim Herz, Gang Yu

Research output: Contribution to journalReview articlepeer-review

157 Scopus citations


The RNA-binding protein TDP-43 is strongly linked to neurodegeneration. Not only are mutations in the gene encoding TDP-43 associated with ALS and FTLD, but this protein is also a major constituent of pathological intracellular inclusions in these diseases. Recent studies have significantly expanded our understanding of TDP-43 physiology. TDP-43 is now known to play important roles in neuronal RNA metabolism. It binds to and regulates the splicing and stability of numerous RNAs encoding proteins involved in neuronal development, synaptic function and neurodegeneration. Thus, a loss of these essential functions is an attractive hypothesis regarding the role of TDP-43 in neurodegeneration. Moreover, TDP-43 is an aggregation-prone protein and, given the role of toxic protein aggregates in neurodegeneration, a toxic gain-of-function mechanism is another rational hypothesis. Importantly, ALS related mutations modulate the propensity of TDP-43 to aggregate in cell culture. Several recent studies have documented that cytoplasmic TDP-43 aggregates co-localize with stress granule markers. Stress granules are cytoplasmic inclusions that repress translation of a subset of RNAs in times of cellular stress, and several proteins implicated in neurodegeneration (i.e. Ataxin-2 and SMN) interact with stress granules. Thus, understanding the interplay between TDP-43 aggregation, stress granules and the effect of ALS-associated TDP-43 mutations may be the key to understanding the role of TDP-43 in neurodegeneration. We propose two models of TDP-43 aggregate formation. The independent model stipulates that TDP-43 aggregation is independent of stress granule formation, in contrast to the precursor model which presents the idea that stress granule formation contributes to a TDP-43 aggregate seed and that chronic stress leads to concentration-dependent TDP-43 aggregation. This article is part of a Special Issue entitled: RNA-Binding Proteins.

Original languageEnglish (US)
Pages (from-to)16-25
Number of pages10
JournalBrain Research
StatePublished - Jun 26 2012


  • ALS
  • Amyotrophic lateral sclerosis
  • FTD
  • FTLD
  • FUS
  • Frontotemporal lobar degeneration
  • Independent model
  • Neurodegeneration
  • Precursor model
  • Stress granule
  • TDP-43

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology


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