SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F

Fatma Ayhan, Barbara A. Perez, Hannah K. Shorrock, Tao Zu, Monica Banez-Coronel, Tammy Reid, Hirokazu Furuya, H. Brent Clark, Juan C. Troncoso, Christopher A. Ross, S. H. Subramony, Tetsuo Ashizawa, Eric T. Wang, Anthony T. Yachnis, Laura P.W. Ranum

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the in vivo accumulation of CUG RNA foci, an ATG-initiated polyGln and a polyAla protein expressed by repeat-associated non-ATG (RAN) translation. Although RAN proteins have been reported in a growing number of diseases, the mechanisms and role of RAN translation in disease are poorly understood. We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity. WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA8 and identify eIF3F as a novel modulator of RAN protein accumulation.

Original languageEnglish (US)
Article numbere99023
JournalEMBO Journal
Volume37
Issue number19
DOIs
StatePublished - Oct 1 2018

Keywords

  • RAN translation
  • eIF3F
  • polyserine
  • spinocerebellar ataxia type 8 (SCA8)
  • white matter

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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