Gain-of-function screen identifies a role of the Sec61α translocon in Drosophila postmitotic neurotoxicity

Hirotaka Kanuka, Tetsuo Hiratou, Tatsushi Igaki, Hiroshi Kanda, Erina Kuranaga, Kazunobu Sawamoto, Toshiro Aigaki, Hideyuki Okano, Masayuki Miura

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

To elucidate the intrinsic mechanisms of neurotoxicity induction, including those underlying neural cell death and neurodegeneration, we developed a gain-of-function screen for gene products causing neural cell loss. To identify novel genes with a cell-death-related function in neurons, we screened 4,964 Drosophila GS lines, in which one or two genes from much of the Drosophila genome can be overexpressed. Approximately 0.68% of the GS lines produced phenotypes involving a loss of postmitotic neurons. Of these, we identified and characterized the endd2 gene, which encodes the Drosophila ortholog of Sec61α (DSec61α), an endoplasmic reticulum protein with protein translocation activity. Ectopic expression of DSec61α caused neural cell death accompanied by the accumulation of ubiquitinated proteins, which was mediated by DSec61α's translocon activity. This supported our previous observation that the DSec61α translocon contributes to expanded polyglutamine-mediated neuronal toxicity, which is also associated with ubiquitinated protein accumulation. These data suggest that the translocon may be a novel component of neural cell death and degeneration pathways. Our approach can be used to identify potential neurotoxic factors within the whole genome, which will increase our understanding of the molecular mechanisms of various types of cell death, including those associated with human neurodegenerative diseases.

Original languageEnglish
Pages (from-to)225-237
Number of pages13
JournalBiochimica et Biophysica Acta - General Subjects
Volume1726
Issue number3
DOIs
Publication statusPublished - 2005 Nov 30

Keywords

  • Apoptosis
  • Cell death
  • Drosophila
  • Neurodegeneration
  • Neurotoxicity

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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