ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor

Li Qun Liu-Yesucevitz, Amy Y. Lin, Atsushi Ebata, Joon Y. Boon, Whitney Reid, Ya Fei Xu, Kendra Kobrin, George J. Murphy, Leonard Petrucelli, Benjamin Wolozin

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Trans-activating response region (TAR) DNA-binding protein of 43 kDa (TDP-43) is an RNA-binding protein that is mutated in familial amyotrophic lateral sclerosis (ALS). Disease-linked mutations in TDP-43 increase the tendency of TDP-43 to aggregate, leading to a corresponding increase in formation of stress granules, cytoplasmic protein/RNA complexes that form in response to stress. Although the field has focused on stress granules, TDP-43 also forms other types of RNA granules. For example, TDP-43 is associated with RNA granules that are prevalent throughout the dendritic arbor in neurons. Because aggregation of TDP-43 is also important for the formation of these neuronal RNA granules, we hypothesized that disease-linked mutations might alter granule formation even in the absence of stress. We now report that ALS-linked mutations in TDP-43 (A315T and Q343R) increase the size of neuronal TDP-43 granules in the dendritic arbor of rat hippocampal neurons. The mutations correspondingly reduce the granule density, movement, and mobility of TDP-43 granules. Depolarization of rat hippocampal neurons with KCl stimulates TDP-43 granule migration into dendrites, but A315T and Q343R TDP-43 granules migrate shorter distances and into fewer dendrites than wild-type TDP-43. These findings highlight novel elements of TDP-43 biology that are affected by disease-linked mutations and suggest a neuronally selective mechanism through which TDP-43 mutations might elicit neuronal dysfunction.

Original languageEnglish (US)
Pages (from-to)4167-4174
Number of pages8
JournalJournal of Neuroscience
Volume34
Issue number12
DOIs
StatePublished - Jan 1 2014

Keywords

  • G3BP
  • Induced pluripotent stem cells
  • Stress granule
  • TIA-1
  • Trafficking
  • Translation

ASJC Scopus subject areas

  • Neuroscience(all)

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    Liu-Yesucevitz, L. Q., Lin, A. Y., Ebata, A., Boon, J. Y., Reid, W., Xu, Y. F., Kobrin, K., Murphy, G. J., Petrucelli, L., & Wolozin, B. (2014). ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor. Journal of Neuroscience, 34(12), 4167-4174. https://doi.org/10.1523/JNEUROSCI.2350-13.2014