Protein Misfolding, Amyloid Formation, and Neurodegeneration

Muchowski, Paul J.

doi:10.1016/s0896-6273(02)00761-4

Cited by 293 publications

(191 citation statements)

References 22 publications

Supporting

Mentioning

185

Contrasting

Unclassified

Order By: Relevance

“…Similar behavior may be present intracellularly for different chaperones, e.g. Hsp70 may force amyloidogenic proteins on to the amorphous aggregation pathway [38] where they could be sequestered by the action of sHsps. To determine these various possibilities will require the implementation of a variety of in vitro, cellular and in vivo experiments.…”

Section: Unanswered Questions and Directions For Shsp And Clusterin Rmentioning

confidence: 81%

See 1 more Smart Citation

Small Heat‐shock Proteins and Clusterin: Intra‐ and Extracellular Molecular Chaperones with a Common Mechanism of Action and Function?

et al. 2003

View full text Add to dashboard Cite

Small heat-shock proteins (sHsps) and clusterin are molecular chaperones that share many functional similarities despite their lack of significant sequence similarity. These functional similarities, and some differences, are discussed. sHsps are ubiquitous intracellular proteins whereas clusterin is generally found extracellularly. Both chaperones potently prevent the amorphous aggregation and precipitation of target proteins under stress conditions such as elevated temperature, reduction and oxidation. In doing so, they act on the slow off-folding protein pathway. The conformational dynamism and aggregated state of both proteins may be crucial for their chaperone function. Subunit exchange is likely to be important in regulating chaperone action; the dissociated form of the protein is probably the chaperone-active species rather than the aggregated state. They both exert their chaperone action without the need for hydrolysis of ATP and have little ability to refold target proteins. Increased expression of sHsp and clusterin accompanies a range of diseases, e.g. Alzheimer's, Creutzfeldt-Jakob and Parkinson's diseases, that arise from protein misfolding and deposition of highly structured protein aggregates known as amyloid fibrils. The interaction of sHsps and clusterin with fibril-forming species is discussed along with their ability to prevent fibril formation, probably via utilization of their chaperone ability. Disciplines Life Sciences | Physical Sciences and Mathematics | Social and Behavioral Sciences Publication DetailsThis article was originally published as Carver, JA, Rekas, A, Thorn, DC and Wilson, MR, Small heat-shock proteins and clusterin: intra-and extracellular molecular chaperones with a common mechanism of action and function, IUBMB Life, 55, 2003, 661-668 AbstractSmall heat-shock proteins (sHsps) and clusterin are molecular chaperones that share many functional similarities despite their lack of significant sequence similarity. These functional similarities, and some differences, are discussed. sHsps are ubiquitous intracellular proteins whereas clusterin is generally found extracellularly. Both chaperones potently prevent the amorphous aggregation and precipitation of target proteins under stress conditions such as elevated temperature, reduction and oxidation. In doing so, they act on the slow off-folding protein pathway. The conformational dynamism and aggregated state of both proteins may be crucial for their chaperone function. Subunit exchange is likely to be important in regulating chaperone action; the dissociated form of the protein is probably the chaperone-active species rather than the aggregated state. They both exert their chaperone action without the need for hydrolysis of ATP and have little ability to refold target proteins. Increased expression of sHsp and clusterin accompanies a range of diseases, e.g. Alzheimer's, Creutzfeldt-Jakob and Parkinson's diseases, that arise from protein misfolding and deposition of highly structured protein aggregates known as amyloid f...

show abstract

Section: Unanswered Questions and Directions For Shsp And Clusterin Rmentioning

confidence: 81%

“…The involvement of molecular chaperones in these processes provides a possible avenue for therapeutic intervention, e.g. as agents to modulate amyloid fibril formation [38]. [3,15].…”

Section: Unanswered Questions and Directions For Shsp And Clusterin Rmentioning

confidence: 99%

Small Heat‐shock Proteins and Clusterin: Intra‐ and Extracellular Molecular Chaperones with a Common Mechanism of Action and Function?

et al. 2003

View full text Add to dashboard Cite

show abstract

“…prion protein ͉ PrP Sc ͉ Thioflavin T ͉ protease-sensitive ͉ femtogram A lternative folding of proteins features in many neurodegenerative diseases, including Parkinson's, Huntington's, and Alzheimer's, as well as the prion diseases (1)(2)(3). In several of these diseases, the alternatively folded proteins can adopt ␤-sheet-rich conformations that facilitate polymerization into amyloid fibers.…”

mentioning

confidence: 99%

Prion detection by an amyloid seeding assay

Colby

Zhang²,

Wang³

et al. 2007

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

207

185

View full text Add to dashboard Cite

Polymerization of recombinant prion protein (recPrP), which was produced in bacteria, into amyloid fibers was accompanied by the acquisition of prion infectivity. We report here that partially purified preparations of prions seed the polymerization of recPrP into amyloid as detected by a fluorescence shift in the dye Thioflavin T. Our amyloid seeding assay (ASA) detected PrP Sc , the sole component of the prion, in brain samples from humans with sporadic Creutzfeldt–Jakob disease, as well as in rodents with experimental prion disease. The ASA detected a variety of prion strains passaged in both mice and hamsters. The sensitivity of the ASA varied with strain type; for hamster Sc237 prions, the limit of detection was ≈1 fg. Some prion strains consist largely of protease-sensitive PrP Sc (sPrP Sc ), and these strains were readily detected by ASA. Our studies show that the ASA provides an alternative methodology for detecting both sPrP Sc and protease-resistant PrP Sc that does not rely on protease digestion or immunodetection.

show abstract

“…An increasing number of experimental studies show that the accumulation of misfolded proteins results in protein aggregates that cause cell toxicity and eventual cell death (12,13). Chaperones and proteases maintain the concentration of unfolded proteins at low levels.…”

Section: Resultsmentioning

confidence: 99%

Rationalizing translation attenuation in the network architecture of the unfolded protein response

Trusina

Papa

Tang

2008

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

View full text Add to dashboard Cite

Increased levels of unfolded proteins in the endoplasmic reticulum (ER) of all eukaryotes trigger the unfolded protein response (UPR). Lower eukaryotes solely use an ancient UPR mechanism, whereby they up-regulate ER-resident chaperones and other enzymatic activities to augment protein folding and enhance degradation of misfolded proteins. Metazoans have evolved an additional mechanism through which they attenuate translation of secretory pathway proteins by activating the ER protein kinase PERK. In mammalian professional secretory cells such as insulin-producing pancreatic ␤-cells, PERK is highly abundant and crucial for proper functioning of the secretory pathway. Through a modeling approach, we propose explanations for why a translation attenuation (TA) mechanism may be critical for ␤-cells, but is less important in nonsecretory cells and unnecessary in lower eukaryotes such as yeast. We compared the performance of a model UPR, both with and without a TA mechanism, by monitoring 2 variables: (i) the maximal increase in ER unfolded proteins during a response, and (ii) the accumulation of chaperones between 2 consecutive pulses of stress. We found that a TA mechanism is important for minimizing these 2 variables when the ER is repeatedly subjected to transient unfolded protein stresses and when it sustains a large flux of secretory pathway proteins which are both conditions encountered physiologically by pancreatic ␤-cells. Low expression of PERK in nonsecretory cells, and its absence in yeast, can be rationalized by lower trafficking of secretory proteins through their ERs.pancreatic beta cells ͉ modeling ͉ negative feedback loops ͉ stress response

show abstract

Protein Misfolding, Amyloid Formation, and Neurodegeneration

Cited by 293 publications

References 22 publications

Small Heat‐shock Proteins and Clusterin: Intra‐ and Extracellular Molecular Chaperones with a Common Mechanism of Action and Function?

Small Heat‐shock Proteins and Clusterin: Intra‐ and Extracellular Molecular Chaperones with a Common Mechanism of Action and Function?

Prion detection by an amyloid seeding assay

Rationalizing translation attenuation in the network architecture of the unfolded protein response

Contact Info

Product

Resources

About