Chaperone-dependent amyloid assembly protects cells from prion toxicity

Douglas, Peter M.; Treusch, Sebastian; Ren, Hong Yu; Halfmann, Randal; Duennwald, Martin L.; Lindquist, Susan; Cyr, Douglas M.

doi:10.1073/pnas.0802593105

Cited by 161 publications

(251 citation statements)

References 35 publications

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“…Our data strongly suggest that aggregate inclusions, in addition to colocalizing with quality control components, are functional compartments. Other studies have also noted that active aggregation can be protective of cell viability, whereas solubilization of amyloidogenic proteins can actually lead to toxicity (11,34,35). The diverse susceptibility of different cell types to aggregate toxicity necessitates an exploration of the way all cells manage aggregates, in an effort to understand the differences between the general case, and the specific case of neurons afflicted in diseases.…”

Section: Discussionmentioning

confidence: 99%

Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity

Weisberg

Lyakhovetsky

Werdiger

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

125

144

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Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability. aggregation quality control | ALS | insoluble protein deposit | protein folding

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Section: Discussionmentioning

confidence: 99%

Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity

Weisberg

Lyakhovetsky

Werdiger

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

125

144

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“…Broad substrate specificity makes it difficult to target chaperones to specific proteins, and some chaperones seem to promote amyloid formation (57). Therefore, it will be essential to identify chaperones with some level of specificity for A␤ and/or natural co-localization with APP/A␤ and to know at what stage of APP processing and/or A␤ aggregation a specific chaperone might interfere.…”

Section: Discussionmentioning

confidence: 99%

BRICHOS Domains Efficiently Delay Fibrillation of Amyloid β-Peptide

Willander

Presto

Askarieh

et al. 2012

Journal of Biological Chemistry

132

160

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Background: Alzheimer disease (AD) is associated with A␤ protein misfolding and aggregation into fibrils rich in ␤-sheet structure. Results: BRICHOS domains prevent fibril formation of A␤ far below the stoichiometric ratio. Conclusion: A␤ is maintained as an unstructured monomer in the presence of BRICHOS. Significance: BRICHOS domain can have a natural protective role against A␤ aggregation, which may open new routes toward AD therapy.

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“…Of these, the most widely studied both in general and in relation to prion biology are Sis1p, which is essential for viability, and Ydj1p. Sis1p (Sondheimer et al 2001;Douglas et al 2008;Higurashi et al 2008). Upon depletion of Sis1p, [PIN 1 ] and [URE3] prions are lost at a similar rapid rate, but loss of [PSI 1 ] is delayed and more gradual (Higurashi et al 2008).…”

mentioning

confidence: 94%