Polyglutamine aggregates alter protein folding homeostasis in
            <i>Caenorhabditis elegans</i>

Satyal, Sanjeev; Schmidt, Enrico; Kitagawa, Katsumi; Sondheimer, Neal; Lindquist, Susan; Kramer, James M.; Morimoto, Richard I.

doi:10.1073/pnas.100107297

Cited by 356 publications

(282 citation statements)

References 59 publications

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“…The severe aggregation of FlucDM, and to a lesser extent that of FlucSM and Fluc, suggests that the protein quality control machinery is compromised by mutant Htt. Our observation supports previous findings where mutant Htt has been proposed to modulate the folding capacity of cells (Gidalevitz et al, 2006;Satyal et al, 2000). A study by Vendruscolo and co-workers has indicated that proteins are only marginally stable under a given set of conditions where they remain soluble and function efficiently.…”

Section: Vi5 Fluc-based Sensors Report On Proteostasis Collapse By supporting

confidence: 92%

“…Indeed, several studies have shown that sequestration of metastable and essential cellular factors such as proteins involved in chromatin remodeling, transcription, translation, nuclear import and cytoskeletal structure by the aggregates is the major cause of observed toxicity in vivo (Bucciantini et al, 2002;Chai et al, 2002;Olzscha et al, 2011;Suhr et al, 2001). Aggregates can also interfere with the cellular defense mechanisms by altering protein folding homeostasis (Gidalevitz et al, 2006;Satyal et al, 2000), by blocking proteasome mediated degradation (Bence et al, 2001;Bennett et al, 2005) or by inhibiting autophagy . Other models suggest that the aggregates can engage in aberrant interaction with cellular membranes leading to the formation of membrane pores (Lashuel et al, 2002) or they can disturb cellular ion homeostasis (Quist et al, 2005), may cause mitochondrial dysfunction and oxidative stress (Muller et al, 2010) (Figure 8).…”

Section: Prion Protein Extracellularmentioning

confidence: 99%

“…A considerable body of experimental evidence suggests that formation of Htt inclusions is a protective mechanism, employed by cells to sequester potentially dangerous soluble oligomers of misfolded Htt (Arrasate et al, 2004;Bodner et al, 2006;Miller et al, 2010;Takahashi et al, 2008). This sequestration may reduce the number of exposed regions in mutant Htt that otherwise would titrate away cellular folding factors, putting the folding of the metastable proteome in jeopardy (Gidalevitz et al, 2006;Satyal et al, 2000).…”

Section: Ii431 Huntington's Diseasementioning

confidence: 99%

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Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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Section: Vi5 Fluc-based Sensors Report On Proteostasis Collapse By supporting

confidence: 92%

Section: Prion Protein Extracellularmentioning

confidence: 99%

Section: Ii431 Huntington's Diseasementioning

confidence: 99%

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Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…Huntington's disease (HD)], mammalian cell cultures, and yeast models of HD. [16][17][18][19][20] Others have shown that Hsp104 alone can disassemble preformed Sup35 and Ure2 prion fibrils. 2,3 However, the molecular mechanisms underlying these effects remain poorly understood (Scheme 1c).…”

Section: Introductionmentioning

confidence: 99%

Hsp104 Targets Multiple Intermediates on the Amyloid Pathway and Suppresses the Seeding Capacity of Aβ Fibrils and Protofibrils

Arimon

Grimminger

Sanz

et al. 2008

Journal of Molecular Biology

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The heat shock protein Hsp104 has been reported to possess the ability to modulate protein aggregation and toxicity and to "catalyze" the disaggregation and recovery of protein aggregates, including amyloid fibrils, in yeast, Escherichia coli, mammalian cell cultures, and animal models of Huntington's disease and Parkinson's disease. To provide mechanistic insight into the molecular mechanisms by which Hsp104 modulates aggregation and fibrillogenesis, the effect of Hsp104 on the fibrillogenesis of amyloid beta (Aβ) was investigated by characterizing its ability to interfere with oligomerization and fibrillogenesis of different species along the amyloid-formation pathway of Aβ. To probe the disaggregation activity of Hsp104, its ability to dissociate preformed protofibrillar and fibrillar aggregates of Aβ was assessed in the presence and in the absence of ATP. Our results show that Hsp104 inhibits the fibrillization of monomeric and protofibrillar forms of Aβ in a concentration-dependent but ATP-independent manner. Inhibition of Aβ fibrillization by Hsp104 is observable up to Hsp104/Aβ stoichiometric ratios of 1:1000, suggesting a preferential interaction of Hsp104 with aggregation intermediates (e.g., oligomers, protofibrils, small fibrils) on the pathway of Aβ amyloid formation. This hypothesis is consistent with our observations that Hsp104 (i) interacts with Aβ protofibrils, (ii) inhibits conversion of protofibrils into amyloid fibrils, (iii) arrests fibril elongation and reassembly, and (iv) abolishes the capacity of protofibrils and sonicated fibrils to seed the fibrillization of monomeric Aβ. Together, these findings suggest that the strong inhibition of Aβ fibrillization by Hsp104 is mediated by its ability to act at different stages and target multiple intermediates on the pathway to amyloid formation.

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“…The expression of polyglutamine repeats is sufficient to cause neurodegeneration or toxicity in model organisms and cell death in cultured cells (5)(6)(7)(8)(9)(10)(11). The clinical severity and the age of onset of disease symptoms are mainly determined by the length of the polyglutamine in the protein responsible, that is, the longer the polyglutamine, the earlier the onset, and the more severe the disease.…”

mentioning

confidence: 99%

Circumvention of Chaperone Requirement for Aggregate Formation of a Short Polyglutamine Tract by the Co-expression of a Long Polyglutamine Tract

Kimura

Koitabashi

Kakizuka

et al. 2002

Journal of Biological Chemistry

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Polyglutamine disease is now recognized as one of the conformational, amyloid-related diseases. In this disease, polyglutamine expansion in proteins has toxic effects on cells and also results in the formation of aggregates. Polyglutamine aggregate formation is accompanied by conversion of the polyglutamine from a soluble to an insoluble form. In yeast, the efficiency of the aggregate formation is determined by the balance of various parameters, including the length of the polyglutamine tract, the function of Hsp104, and the level of polyglutamine expression. In this study, we found that the co-expression of a long polyglutamine tract, which formed aggregates independently of the function of Hsp104, enhanced the formation of aggregates of a short polyglutamine tract in wild-type cells as well as in ⌬hsp104 mutant cells. Thus, the expression of a long polyglutamine tract would be an additional parameter determining the efficiency of aggregate formation of a short polyglutamine tract. The co-localization of aggregates of long and short polyglutamine tracts suggests the possibility that the enhancement occurs due to the seeding of aggregates of the long polyglutamine tracts.Expansion of polyglutamine repeats in a protein has now been proved to account for the pathogenesis of at least nine inherited neurodegenerative diseases, including spinobulbar muscular atrophy, Huntington's disease, spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17 (SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and SCA17, respectively), and dentatorubural pallidoluysian atrophy (1-4). The expression of polyglutamine repeats is sufficient to cause neurodegeneration or toxicity in model organisms and cell death in cultured cells (5-11). The clinical severity and the age of onset of disease symptoms are mainly determined by the length of the polyglutamine in the protein responsible, that is, the longer the polyglutamine, the earlier the onset, and the more severe the disease. Moreover, the deposition of aggregates that contain the expanded polyglutamine is a hallmark of the affected organs and dying cells, and the ability of the expanded polyglutamine to induce these toxic phenomena appears to be inseparably linked with its ability to form aggregates. Thus, the conformational change of the expanded polyglutamine is likely a pathogenic mechanism causing these diseases, although whether the aggregates themselves are pathogenic or not is unknown. Moreover, staining of the brain of Huntington's disease patients with Congo Red suggests that polyglutamine diseases are associated with amyloid fibrils (12).Polyglutamine aggregate formation of amyloid-like appearance has been observed in vitro (13-15). These studies indicate that aggregate formation is autonomous in vitro in the length-, concentration-, and time-dependent manner of a polyglutamine. However, in vivo, in yeast, polyglutamine aggregate formation requires the function of the molecular chaperone Hsp104, a member of the AAA ϩ superfamily, in addition to the parameters noted above (16,17). Upon induction of...

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Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans

Cited by 356 publications

References 59 publications

Firefly luciferase mutants as sensors of proteome stress

Firefly luciferase mutants as sensors of proteome stress

Hsp104 Targets Multiple Intermediates on the Amyloid Pathway and Suppresses the Seeding Capacity of Aβ Fibrils and Protofibrils

Circumvention of Chaperone Requirement for Aggregate Formation of a Short Polyglutamine Tract by the Co-expression of a Long Polyglutamine Tract

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