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SCA 8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF 3F
Author(s) -
Ayhan Fatma,
Perez Barbara A,
Shorrock Hannah K,
Zu Tao,
BanezCoronel Monica,
Reid Tammy,
Furuya Hirokazu,
Clark H Brent,
Troncoso Juan C,
Ross Christopher A,
Subramony SH,
Ashizawa Tetsuo,
Wang Eric T,
Yachnis Anthony T,
Ranum Laura PW
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899023
Subject(s) - biology , ran , microbiology and biotechnology
Spinocerebellar ataxia type 8 ( SCA 8) 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 SCA 8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF 3F in cells reduces steady‐state levels of SCA 8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA 8 and identify eIF 3F as a novel modulator of RAN protein accumulation.