PolyQ Expansion Controls Biomolecular Condensation and Aggregation of the N-Terminal Fragments of Ataxin-2

Ataxin-2 (Atx2) is a general RNA-binding protein involved in processes such as RNA processing and metabolism in cells. Atx2 is also a polyglutamine (polyQ) tract-containing protein; its abnormal expansion can lead to protein aggregation associated with neurodegenerative diseases. Previous studies have shown that the C-terminal intrinsically disordered regions (c-IDRs) of Atx2 participate in its condensation and aggregation processes. To elucidate the role of polyQ expansion in biomolecular condensation and aggregation, we studied the N-terminal fragments of Atx2 (namely, Atx2-N317 and Atx2-N81) that preserve a polyQ tract and compared their molecular behaviors in cells to those of the full-length Atx2. We found that the molecular mobility of the N-terminal fragments decreases with the increasing length of polyQ, indicating that polyQ expansion promotes a gradual phase transition to an irreversible and insoluble state. Moreover, the molecular state and mobility of Atx2-N317 are not distinct from those of Atx2-N81, regardless of the presence of other domains, demonstrating that the polyQ tract is a direct and sufficient element for protein condensation and aggregation, while the Like Sm (LSm) and LSm-associated (LSmAD) domains and their interactions with RNA are not necessary for these processes. This result is also validated through the in vitro investigation of Atx2-N81 with different polyQ expansions. This study reveals that polyQ expansion controls the biomolecular condensation and aggregation of the N-terminal fragments of Atx2 and is thus thought to modulate the dynamic behaviors of the full-length protein as well, which is implicated in the pathological accumulation of Atx2 in cells.