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 Pw Ranum

doi:10.15252/embj.201899023

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

EMBO J. 2018 Oct 1;37(19):e99023. doi: 10.15252/embj.201899023. Epub 2018 Sep 11.

Authors

Fatma Ayhan^{1

2}, Barbara A Perez^{1

2}, Hannah K Shorrock^{1

2}, Tao Zu^{1

2}, Monica Banez-Coronel^{1

2}, Tammy Reid^{1

2}, Hirokazu Furuya^{3

4}, H Brent Clark⁵, Juan C Troncoso⁶, Christopher A Ross^{7

8

9

10

11}, S H Subramony^{1

12}, Tetsuo Ashizawa¹³, Eric T Wang^{1

2}, Anthony T Yachnis¹⁴, Laura Pw Ranum^{15

2

12

16}

Affiliations

¹ Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL, USA.
² Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA.
³ Department of Neurology, Kochi Medical School, Kochi University, Kochi, Japan.
⁴ Department of Neurology, Neuro-Muscular Center, NHO Omuta Hospital, Fukuoka, Japan.
⁵ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA.
⁶ Department of Pathology and Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Huntington's Disease Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, USA.
¹³ Department of Neurology, Houston Methodist Hospital, Houston, TX, USA.
¹⁴ Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
¹⁵ Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL, USA ranum@ufl.edu.
¹⁶ Genetics Institute, University of Florida, Gainesville, FL, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

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

Authors

Affiliations

Abstract

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MeSH terms

Substances

Supplementary concepts

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