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

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.

• Authors: 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 Pw Ranum
• Journal: The EMBO journal (EMBO J) Vol. 37 Issue 19 (10 01 2018) ISSN: 1460-2075 [Electronic] England
• PMID: 30206144 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors.

Chemical References

• Eukaryotic Initiation Factor-3
• Nerve Tissue Proteins

Topics

• Aging (genetics, metabolism, pathology)
• Animals
• Eukaryotic Initiation Factor-3 (genetics, metabolism)
• HeLa Cells
• Humans
• Mice
• Mice, Transgenic
• Nerve Tissue Proteins (genetics, metabolism)
• Spinocerebellar Degenerations (genetics, metabolism, pathology)
• White Matter (metabolism, pathology)