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

doi:10.15252/embj.201899023

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

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45 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 language	English (US)
Article number	e99023
Journal	EMBO Journal
Volume	37
Issue number	19
DOIs	https://doi.org/10.15252/embj.201899023
State	Published - Oct 1 2018

Keywords

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

ASJC Scopus subject areas

General Neuroscience
Molecular Biology
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.15252/embj.201899023

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Ayhan, F., Perez, B. A., Shorrock, H. K., Zu, T., Banez-Coronel, M., Reid, T., Furuya, H., Clark, H. B., Troncoso, J. C., Ross, C. A., Subramony, S. H., Ashizawa, T., Wang, E. T., Yachnis, A. T., & Ranum, L. P. W. (2018). SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F. EMBO Journal, 37(19), Article e99023. https://doi.org/10.15252/embj.201899023

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title = "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.",

keywords = "RAN translation, eIF3F, polyserine, spinocerebellar ataxia type 8 (SCA8), white matter",

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

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language = "English (US)",

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AU - Ayhan, Fatma

AU - Perez, Barbara A.

AU - Shorrock, Hannah K.

AU - Zu, Tao

AU - Banez-Coronel, Monica

AU - Reid, Tammy

AU - Furuya, Hirokazu

AU - Clark, H. Brent

AU - Troncoso, Juan C.

AU - Ross, Christopher A.

AU - Subramony, S. H.

AU - Ashizawa, Tetsuo

AU - Wang, Eric T.

AU - Yachnis, Anthony T.

AU - Ranum, Laura P.W.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

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KW - spinocerebellar ataxia type 8 (SCA8)

KW - white matter

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

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