RNA binding mediates neurotoxicity in the transgenic Drosophila model of TDP-43 proteinopathy

Ryoko Ihara, Koji Matsukawa, Yusei Nagata, Hayato Kunugi, Shoji Tsuji, Takahiro Chihara, Erina Kuranaga, Masayuki Miura, Tomoko Wakabayashi, Tadafumi Hashimoto, Takeshi Iwatsubo

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive and selective loss ofmotor neurons.Thediscovery of mutations in thegeneencodinganRNA-bindingprotein,TARDNA-binding protein of 43 kD (TDP-43), in familial ALS, strongly implicated abnormalities inRNA processing in the pathogenesis of ALS, although the mechanisms whereby TDP-43 leads to neurodegeneration remain elusive. To clarify the mechanism of degeneration caused by TDP-43, we generated transgenic Drosophila melanogaster expressing a series of systematically modified human TDP-43 genes in the retinal photoreceptor neurons. Overexpression of wild-type TDP-43 resultedinvacuolar degeneration of the photoreceptor neurons associated with thinning of the retina, which was significantly exacerbated bymutations of TDP-43 linked to familial ALS or disrupting its nuclear localization signal (NLS). Remarkably, these degenerative phenotypes were completely normalized by addition of a mutation or deletion of the RNA recognition motif that abolishes the RNA binding ability of TDP-43. Altogether, our results suggest that RNA binding is key to the neurodegeneration caused by overexpression of TDP-43, and that abnormalities in RNA processing may be crucial to the pathogenesis of TDP-43 proteinopathy.

Original languageEnglish
Article numberddt296
Pages (from-to)4474-4484
Number of pages11
JournalHuman molecular genetics
Issue number22
Publication statusPublished - 2013 Nov
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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