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 language | English (US) |
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Article number | e99023 |
Journal | EMBO Journal |
Volume | 37 |
Issue number | 19 |
DOIs | |
State | Published - Oct 1 2018 |
Bibliographical note
Funding Information:We thank the families that donated tissue for making this research possible. This work was funded by the National Ataxia Foundation (L.P.W.R.) and the NIH (5R37NS040389-13) (L.P.W.R.), a University of Florida Alumni Fellowship (F.A.), an NIH T32 Training Grant (NS082168) (B.A.P.), the 1-Florida ADRC (NIH P50 AG047266-01A1) (A.T.Y), and the Johns Hopkins University Alzheimer's Disease Research Center (NIH P50AG05146) (J.C.T. and C.A.R).
Funding Information:
We thank the families that donated tissue for making this research possible. This work was funded by the National Ataxia Foundation (L.P.W.R.) and the NIH (5R37NS040389-13) (L.P.W.R.), a University of Florida Alumni Fellowship (F.A.), an NIH T32 Training Grant (NS082168) (B.A.P.), the 1-Florida ADRC (NIH P50 AG047266-01A1) (A.T.Y), and the Johns Hopkins University Alzheimer’s Disease Research Center (NIH P50AG05146) (J.C.T. and C.A.R).
Publisher Copyright:
© 2018 The Authors
Keywords
- RAN translation
- eIF3F
- polyserine
- spinocerebellar ataxia type 8 (SCA8)
- white matter