Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington’s disease pathology

Scherzinger, Eberhard; Sittler, Annie; Schweiger, Katja; Heiser, Volker; Lurz, Rudi; Hasenbank, Renate; Bates, Gillian P.; Lehrach, Hans; Wanker, Erich E.

doi:10.1073/pnas.96.8.4604

Cited by 664 publications

(691 citation statements)

References 33 publications

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“…[104]. The length of the expanded polyQ stretch (38-100 Q and more) correlates with increased aggregation propensity [105] and is inversely correlated with the age of disease onset [106].…”

Section: Resultsmentioning

confidence: 99%

Proteostasis impairment in protein-misfolding and -aggregation diseases

Hipp

Park

Hartl

2014

Trends in Cell Biology

563

486

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Cells possess an extensive network of components to safeguard proteome integrity and maintain protein homeostasis (proteostasis). When this proteostasis network (PN) declines in performance, as may be the case during aging, newly synthesized proteins are no longer able to fold efficiently and metastable proteins lose their functionally active conformations, particularly under conditions of cell stress. Apart from loss-of-function effects, a critical consequence of PN deficiency is the accumulation of cytotoxic protein aggregates, which are also associated with many age-dependent neurodegenerative diseases and other medical disorders. Here we discuss recent evidence that the chronic production of aberrantly folded and aggregated proteins in these diseases is harmful by overtaxing PN capacity, setting in motion a vicious cycle of increasing proteome imbalance that eventually leads to PN collapse and cell death

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“…[104]. The length of the expanded polyQ stretch (38-100 Q and more) correlates with increased aggregation propensity [105] and is inversely correlated with the age of disease onset [106].…”

Section: Resultsmentioning

confidence: 99%

Proteostasis impairment in protein-misfolding and -aggregation diseases

Hipp

Park

Hartl

2014

Trends in Cell Biology

563

486

View full text Add to dashboard Cite

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“…Furthermore a polyglutamine (Gln40) peptide produced homogeneous pore-like protofibrillar structures in vitro, while a shortened peptide did not (Monoi et al 2000). Importantly, b-sheet formation, oligomerization, amyloid pore/channel formation, and fibrillogenesis are also very sensitive to polyGln repeat length (Scherzinger et al 1999). Circumstantial evidence suggests that membrane disruption is mediated by direct interaction between the polyglutamine repeats or an aggregated form of these proteins resulting in the formation of ion channels in lipid bilayers and in mitochondrial membranes.…”

Section: Polyglutamine ' Channels 'mentioning

confidence: 99%

“…A normal transmembrane domain composed of an a-helix is y20 amino acids long. However, b-sheet formation, oligomerization and fibrillogenesis by poly-glutamine proteins are highly dependent on the polyQ repeat length with 36 or more glutamines favoring these tertiary and quaternary structure changes (Scherzinger et al 1999). However, further studies are required to elucidate the nature of the membrane active species responsible for polyglutamine membrane disruption properties.…”

Section: Polyglutamine ' Channels 'mentioning

confidence: 99%

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

Lashuel

Lansbury

2006

Quart. Rev. Biophys.

377

368

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Abstract. Protein fibrillization is implicated in the pathogenesis of most, if not all, ageassociated neurodegenerative diseases, but the mechanism(s) by which it triggers neuronal death is unknown. Reductionist in vitro studies suggest that the amyloid protofibril may be the toxic species and that it may amplify itself by inhibiting proteasome-dependent protein degradation. Although its pathogenic target has not been identified, the properties of the protofibril suggest that neurons could be killed by unregulated membrane permeabilization, possibly by a type of protofibril referred to here as the ' amyloid pore'. The purpose of this review is to summarize the existing supportive circumstantial evidence and to stimulate further studies designed to test the validity of this hypothesis.

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“…Despite the impressive progress made by Wetzel [45,54,[65][66][67] and others [68][69][70][71][72] in the area of polyglutamine aggregation, there are significant gaps in our knowledge because not much is known about intermolecular associations and intramolecular conformational fluctuations that occur at very low protein concentrations (nM -μM). This knowledge is of utmost importance to understand the phenomenon of polyglutamine aggregation in vivo.…”

Section: Unresolved Issues In the Study Of Aggregation-prone Idpsmentioning

confidence: 99%

A polymer physics perspective on driving forces and mechanisms for protein aggregation

Pappu

Wang

Vitalis

et al. 2008

Archives of Biochemistry and Biophysics

156

172

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Protein aggregation is a commonly occurring problem in biology. Cells have evolved stress-response mechanisms to cope with problems posed by protein aggregation. Yet, these quality control mechanisms are overwhelmed by chronic aggregation-related stress and the resultant consequences of aggregation become toxic to cells. As a result, a variety of systemic and neurodegenerative diseases are associated with various aspects of protein aggregation and rational approaches to either inhibit aggregation or manipulate the pathways to aggregation might lead to an alleviation of disease phenotypes. To develop such approaches, one needs a rigorous and quantitative understanding of protein aggregation. Much work has been done in this area. However, several unanswered questions linger, and these pertain primarily to the actual mechanism of aggregation as well as to the types of intermolecular associations and intramolecular fluctuations realized at low protein concentrations. It has been suggested that the concepts underlying protein aggregation are similar to those used to describe the aggregation of synthetic polymers. Following this suggestion, the relevant concepts of polymer aggregation are introduced. The focus is on explaining the driving forces for polymer aggregation and how these driving forces vary with chain length and solution conditions. It is widely accepted that protein aggregation is a nucleation-dependent process. This view is based mainly on the presence of long times for the accumulation of aggregates and the elimination of these lag times with "seeds". In this sense, protein aggregation is viewed as being analogous to the aggregation of colloidal particles. The theories for polymer aggregation reviewed in this work suggest an alternative mechanism for the origin of long lag times in protein aggregation. The proposed mechanism derives from the recognition that polymers have unique dynamics that distinguish them from other aggregation-prone systems such as colloidal particles.

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Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington’s disease pathology

Cited by 664 publications

References 33 publications

Proteostasis impairment in protein-misfolding and -aggregation diseases

Proteostasis impairment in protein-misfolding and -aggregation diseases

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

A polymer physics perspective on driving forces and mechanisms for protein aggregation

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