Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation

Alyssa N. Coyne, Shizuka B. Yamada, Bhavani Bagevalu Siddegowda, Patricia S. Estes, Benjamin L. Zaepfel, Jeffrey S. Johannesmeyer, Donovan B. Lockwood, Linh T. Pham, Michael P. Hart, Joel A. Cassel, Brian Freibaum, Ashley V. Boehringer, J. Paul Taylor, Allen B. Reitz, Aaron D. Gitler, Daniela C. Zarnescu

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

RNA dysregulation is a newly recognized disease mechanism in amyotrophic lateral sclerosis (ALS). Here we identify Drosophila fragile X mental retardation protein (dFMRP) as a robust genetic modifier of TDP-43-dependent toxicity in a Drosophila model of ALS.We find that dFMRP overexpression (dFMRP OE) mitigates TDP-43 dependent locomotor defects and reduced lifespan in Drosophila. TDP-43 and FMRP form a complex in flies and human cells. In motor neurons, TDP-43 expression increases the association of dFMRP with stress granules and colocalizes with polyA binding protein in a variant-dependent manner. Furthermore, dFMRP dosage modulates TDP-43 solubility and molecular mobility with overexpression of dFMRP resulting in a significant reduction of TDP-43 in the aggregate fraction. Polysome fractionation experiments indicate that dFMRP OE also relieves the translation inhibition of futsch mRNA, a TDP-43 target mRNA, which regulates neuromuscular synapse architecture. Restoration of futsch translation by dFMRP OE mitigates Futsch-dependent morphological phenotypes at the neuromuscular junction including synaptic size and presence of satellite boutons. Our data suggest a model whereby dFMRP is neuroprotective by remodeling TDP-43 containing RNA granules, reducing aggregation and restoring the translation of specific mRNAs in motor neurons.

Original languageEnglish (US)
Pages (from-to)6886-6898
Number of pages13
JournalHuman molecular genetics
Volume24
Issue number24
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Coyne, A. N., Yamada, S. B., Siddegowda, B. B., Estes, P. S., Zaepfel, B. L., Johannesmeyer, J. S., Lockwood, D. B., Pham, L. T., Hart, M. P., Cassel, J. A., Freibaum, B., Boehringer, A. V., Paul Taylor, J., Reitz, A. B., Gitler, A. D., & Zarnescu, D. C. (2015). Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation. Human molecular genetics, 24(24), 6886-6898. https://doi.org/10.1093/hmg/ddv389