TY  - JOUR
A1  - Hinz, Justyna
A1  - Lehnhardt, Lothar
A1  - Zakrzewski, Silke
A1  - Zhang, Gong
A1  - Ignatova, Zoya
T1  - Polyglutamine expansion alters the dynamics and molecular architecture of aggregates in dentatorubropallidoluysian atrophy
JF  - The journal of biological chemistry
N2  - 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.
Y1  - 2012
U6  - https://doi.org/10.1074/jbc.M111.318915
SN  - 0021-9258
VL  - 287
IS  - 3
SP  - 2068
EP  - 2078
PB  - American Society for Biochemistry and Molecular Biology
CY  - Bethesda
ER  -