Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31

Taro Ishiguro, Nozomu Sato, Morio Ueyama, Nobuhiro Fujikake, Chantal Sellier, Akemi Kanegami, Eiichi Tokuda, Bita Zamiri, Terence Gall-Duncan, Mila Mirceta, Yoshiaki Furukawa, Takanori Yokota, Keiji Wada, J. Paul Taylor, Christopher E. Pearson, Nicolas Charlet-Berguerand, Hidehiro Mizusawa, Yoshitaka Nagai, Kinya Ishikawa

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)


Microsatellite expansion disorders are pathologically characterized by RNA foci formation and repeat-associated non-AUG (RAN) translation. However, their underlying pathomechanisms and regulation of RAN translation remain unknown. We report that expression of expanded UGGAA (UGGAAexp) repeats, responsible for spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes neurodegeneration accompanied by accumulation of UGGAAexp RNA foci and translation of repeat-associated pentapeptide repeat (PPR) proteins, consistent with observations in SCA31 patient brains. We revealed that motor-neuron disease (MND)-linked RNA-binding proteins (RBPs), TDP-43, FUS, and hnRNPA2B1, bind to and induce structural alteration of UGGAAexp. These RBPs suppress UGGAAexp-mediated toxicity in Drosophila by functioning as RNA chaperones for proper UGGAAexp folding and regulation of PPR translation. Furthermore, nontoxic short UGGAA repeat RNA suppressed mutated RBP aggregation and toxicity in MND Drosophila models. Thus, functional crosstalk of the RNA/RBP network regulates their own quality and balance, suggesting convergence of pathomechanisms in microsatellite expansion disorders and RBP proteinopathies.

Original languageEnglish
Pages (from-to)108-124.e7
Issue number1
Publication statusPublished - 5 Apr 2017
Externally publishedYes


  • ALS
  • Drosophila melanogaster
  • microsatellite repeat expansion diseases
  • RAN translation
  • ribonucleoprotein
  • RNA chaperone
  • RNA foci
  • SCA31
  • TDP-43


Dive into the research topics of 'Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31'. Together they form a unique fingerprint.

Cite this