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SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F
Authors:Hannah K Shorrock  Tao Zu  Monica Banez‐Coronel  Tammy Reid  Hirokazu Furuya  H Brent Clark  Juan C Troncoso  Christopher A Ross  SH Subramony  Tetsuo Ashizawa  Eric T Wang  Anthony T Yachnis  Laura PW Ranum
Affiliation: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. 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:eIF3F  polyserine  RAN translation  spinocerebellar ataxia type 8 (SCA8)  white matter
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