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

Determining if repeat-associated non-AUG (RAN) proteins contribute to the CAG-polyglutamine (polyGln)-encoding spinocerebellar ataxias (CAG-SCAs) is critical for understanding disease mechanisms and for therapy development. Immunohistochemistry shows that sense polyserine (polySer) (AGC frame) and antisense polyleucine (polyLeu) (CUG frame) RAN protein aggregates accumulate throughout the cerebellum and pons, in SCA1, SCA2, SCA3, SCA6, and SCA7 autopsy brains, and in damaged neurons. Cerebellar white matter regions, with prominent polySer and polyLeu but minimal polyGln, show neuroinflammation and demyelination. In SCA3 mice, RAN protein aggregates increase with age. SCA1 Pcp2-ATXN1[82Q] (Pcp2-82Q) mice designed to express ataxin-1 (ATXN1)-polyGln in Purkinje cells show sense and antisense RAN protein aggregates throughout the cerebellum. Disrupting the ATXN182Q:capicua binding, which improves behavior and neuropathology, also reduces RAN protein aggregates. In neural cells, toxic polySer and polyLeu proteins impair autophagy, and reducing RAN protein levels with metformin reduces cytotoxicity. These data identify sense and antisense RAN proteins as a common molecular mechanism shared by the CAG-SCAs.