Polyglutamine Expansion Alters the Dynamics and Molecular Architecture of Aggregates in Dentatorubropallidoluysian Atrophy

Preferential accumulation of mutant proteins in the nucleus has been suggested to be the molecular culprit that confers cellular toxicity in the neurodegenerative disorders caused by polyglutamine (polyQ) expansion. Here, we use dynamic imaging approaches, orthogonal cross-seeding, and composition analysis to examine the dynamics and structure of nuclear and cytoplasmic inclusions of atrophin-1, implicated in dentatorubropallidoluysian atrophy, a polyQ-based disease with complex clinical features. Our results reveal a large heterogeneity in the dynamics of the nuclear inclusions compared with the compact and immobile cytoplasmic aggregates. At least two types of inclusions of expanded atrophin-1 with different mobility of the molecular species and ability to exchange with the surrounding monomer pool coexist in the nucleus. Intriguingly, the enrichment of nuclear inclusions with slow dynamics parallels changes in the aggregate core architecture that are dominated by the polyQ stretch. We propose that the observed complexity in the dynamics of the nuclear inclusions provides a molecular explanation for the enhanced cellular toxicity of the nuclear aggregates in polyQ-based neurodegeneration. Background: Expansion of a polyglutamine repeat in atrophin-1 causes progressive neuronal dysfunction in neurodegenerative dentatorubropallidoluysian atrophy. Results: Nuclear inclusions of expanded atrophin-1 are more dynamic compared with the cytoplasmic aggregates. Conclusion: Structural variations of the aggregate core determine these dynamics. Significance: Probing the molecular properties of the inclusions is crucial for understanding the enhanced cellular toxicity of nuclear aggregates in polyglutamine pathologies.