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

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. Synopsis A novel toxic polySer repeat associated non‐ATG (RAN) translated protein accumulates in white matter regions of the brain in spinocerebellar ataxia type 8 (SCA8) and is linked to demyelination and axonal degeneration. Novel SCA8 polySer RAN protein accumulates in SCA8 human and mouse brains. SCA8 polySer RAN protein aggregates increase with age and disease progression in SCA8 BAC mice. SCA8 RAN polySer aggregates show preferential accumulation in white matter. White matter regions with RAN polySer aggregates show demyelination, axonal degeneration, and oligodendrocyte loss. Knockdown of eIF3F, a translation factor expressed at elevated levels in white matter, reduces the levels of RAN but not AUG‐initiated expansion proteins. Graphical Abstract A novel polySer protein produced by non‐ATG translation of repeat‐expanded mRNA is observed in spinocerebellar ataxia type 8, where it exerts toxic effects on demyelination and axonal degeneration in patient brains.