Repeat associated non-AUG translation as a common mechanism for the polyGln ataxias

Banez-Coronel, M.; Zu, T.; Aldridge, M.; Guo, S.; Ajredini, R.; Morrison, D.; Tays, A. B.; Pletnikova, O.; Yachnis, A. T.; Troncoso, J.; Paulson, H. L.; McLoughlin, H. S.; Ashizawa, T.; Subramony, S. H.; Ranum, L.

doi:10.1101/2025.10.14.682372

bioRxiv · 10.1101/2025.10.14.682372

Repeat associated non-AUG translation as a common mechanism for the polyGln ataxias

Banez-Coronel, M.·Zu, T.·Aldridge, M.·Guo, S.·Ajredini, R.·Morrison, D.·Tays, A. B.·Pletnikova, O.·Yachnis, A. T.·Troncoso, J.·Paulson, H. L.·McLoughlin, H. S.·Ashizawa, T.·Subramony, S. H.·Ranum, L.

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Abstract

Determining if repeat associated non-AUG (RAN) proteins contribute to the CAG polyGln-encoding spinocerebellar ataxias (CAG-SCAs) is critical for understanding mechanisms and developing therapies for these diseases. Immunohistochemistry using antibodies against polySer and polyLeu repeats and locus specific C-terminal regions show sense polySer (AGC frame) and antisense polyLeu (CUG frame) RAN proteins accumulate in affected grey and white-matter brain regions, throughout the cerebellum and pons, in SCA1, SCA2, SCA3, SCA6, and SCA7 autopsy brains. Cerebellar white matter regions with prominent polySer and polyLeu but minimal polyGln aggregates show demyelination, white matter loss, and activated microglia. In SCA3 mice, RAN proteins accumulate in an age-dependent manner. In neural cells, polySer and polyLeu RAN proteins are toxic and cause autophagic dysfunction. In cells, the FDA-approved drug metformin decreases RAN protein levels and reduces toxicity. Taken together, these data identify sense and antisense RAN proteins as a common molecular mechanism shared by the CAG-SCAs.

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Banez-Coronel, M., Zu, T., Aldridge, M., Guo, S., Ajredini, R., Morrison, D., Tays, A. B., Pletnikova, O., Yachnis, A. T., Troncoso, J., Paulson, H. L., McLoughlin, H. S., Ashizawa, T., Subramony, S. H., Ranum, L.. 2025-10-15. Repeat associated non-AUG translation as a common mechanism for the polyGln ataxias. https://doi.org/10.1101/2025.10.14.682372

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