title: Chaperones in Polyglutamine Aggregation: Beyond the Q-Stretch.
abstract: Expanded polyglutamine (polyQ) stretches in at least nine unrelated proteins lead to inherited neuronal dysfunction and degeneration. The expansion size in all diseases correlates with age at onset (AO) of disease and with polyQ protein aggregation, indicating that the expanded polyQ stretch is the main driving force for the disease onset. Interestingly, there is marked interpatient variability in expansion thresholds for a given disease. Between different polyQ diseases the repeat length vs. AO also indicates the existence of modulatory effects on aggregation of the upstream and downstream amino acid sequences flanking the Q expansion. This can be either due to intrinsic modulation of aggregation by the flanking regions, or due to differential interaction with other proteins, such as the components of the cellular protein quality control network. Indeed, several lines of evidence suggest that molecular chaperones have impact on the handling of different polyQ proteins. Here, we review factors differentially influencing polyQ aggregation: the Q-stretch itself, modulatory flanking sequences, interaction partners, cleavage of polyQ-containing proteins, and post-translational modifications, with a special focus on the role of molecular chaperones. By discussing typical examples of how these factors influence aggregation, we provide more insight on the variability of AO between different diseases as well as within the same polyQ disorder, on the molecular level.
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen Groningen, Netherlands.
authors.forename: E F E
authors.initials: EF
authors.lastname: Kuiper
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of GroningenGroningen, Netherlands; Programa de Pós-Graduação em Genética e Biologia Molecular, Department of Genetics, Universidade Federal do Rio Grande do SulPorto Alegre, Brazil; Medical Genetics Service, Hospital de Clínicas de Porto AlegrePorto Alegre, Brazil.
authors.forename: Eduardo P
authors.initials: EP
authors.lastname: de Mattos
authors.affiliation: Programa de Pós-Graduação em Genética e Biologia Molecular, Department of Genetics, Universidade Federal do Rio Grande do SulPorto Alegre, Brazil; Medical Genetics Service, Hospital de Clínicas de Porto AlegrePorto Alegre, Brazil; Departamento de Medicina Interna, Universidade Federal do Rio Grande do SulPorto Alegre, Brazil.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Jardim
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen Groningen, Netherlands.
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen Groningen, Netherlands.
authors.forename: Steven
authors.initials: S
authors.lastname: Bergink
keywords: Huntington's disease; Machado-Joseph disease; aggregation; molecular chaperones; polyglutamine disease