title: Polyglutamine expansion alters the dynamics and molecular architecture of aggregates in dentatorubropallidoluysian atrophy.
abstract: 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.
authors.affiliation: Institute of Biochemistry and Biology, University of Potsdam, 14467 Potsdam, Germany.
authors.forename: Justyna
authors.initials: J
authors.lastname: Hinz
authors.forename: Lothar
authors.initials: L
authors.lastname: Lehnhardt
authors.forename: Silke
authors.initials: S
authors.lastname: Zakrzewski
authors.forename: Gong
authors.initials: G
authors.lastname: Zhang
authors.forename: Zoya
authors.initials: Z
authors.lastname: Ignatova
mesh_terms: D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D010455:Peptides; C095278:atrophin-1; C097188:polyglutamine