Molecular and cellular aspects of protein misfolding and disease

Herczenik, Eszter; Gebbink, Martijn F.B.G.

doi:10.1096/fj.07-099671

Cited by 181 publications

(117 citation statements)

References 276 publications

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“…Misfolded proteins can occur in a variety of forms, such as amorphous aggregates and large amyloid fibrils (21,22). Since both these forms are present in systemic amyloidosis patients, we also wanted to know which form of a misfolded protein induces FXII activation.…”

Section: Resultsmentioning

confidence: 99%

Misfolded proteins activate Factor XII in humans, leading to kallikrein formation without initiating coagulation

et al. 2008

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When blood is exposed to negatively charged surface materials such as glass, an enzymatic cascade known as the contact system becomes activated. This cascade is initiated by autoactivation of Factor XII and leads to both coagulation (via Factor XI) and an inflammatory response (via the kallikrein-kinin system). However, while Factor XII is important for coagulation in vitro, it is not important for physiological hemostasis, so the physiological role of the contact system remains elusive. Using patient blood samples and isolated proteins, we identified a novel class of Factor XII activators. Factor XII was activated by misfolded protein aggregates that formed by denaturation or by surface adsorption, which specifically led to the activation of the kallikreinkinin system without inducing coagulation. Consistent with this, we found that Factor XII, but not Factor XI, was activated and kallikrein was formed in blood from patients with systemic amyloidosis, a disease marked by the accumulation and deposition of misfolded plasma proteins. These results show that the kallikrein-kinin system can be activated by Factor XII, in a process separate from the coagulation cascade, and point to a protective role for Factor XII following activation by misfolded protein aggregates.

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Section: Resultsmentioning

confidence: 99%

Misfolded proteins activate Factor XII in humans, leading to kallikrein formation without initiating coagulation

et al. 2008

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“…At least 30000 different proteins with a different role are identified in humans [99] . The main functions of proteins in all organisms are to make cellular building blocks and to operate cellular functions.…”

Section: Temperature Protein Misfolding Diseases and Longevitymentioning

confidence: 99%

Longevity of animals under reactive oxygen species stress and disease susceptibility due to global warming

Paital

Panda

Hati

et al. 2016

WJBC

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The world is projected to experience an approximate doubling of atmospheric CO2 concentration in the next decades. Rise in atmospheric CO2 level as one of the most important reasons is expected to contribute to raise the mean global temperature 1.4 ℃-5.8 ℃ by that time. A survey from 128 countries speculates that global warming is primarily due to increase in atmospheric CO2 level that is produced mainly by anthropogenic activities. condition induces abnormality in physiology of animals under elevated temperature. Exposure of animals to rise in habitat temperature is found to boost the metabolism of animals and a very strong and positive correlation exists between metabolism and levels of ROS and OS. Continuous induction of OS is negatively correlated with survivability and longevity and positively correlated with ageing in animals. Thus, it can be predicted that continuous exposure of animals to acute or gradual rise in habitat temperature due to global warming may induce OS, reduced survivability and longevity in animals in general and poikilotherms in particular. A positive correlation between metabolism and temperature in general and altered O2 consumption at elevated temperature in particular could also increase the risk of experiencing OS in homeotherms. Effects of global warming on longevity of animals through increased risk of protein misfolding and disease susceptibility due to OS as the cause or effects or both also cannot be ignored. Therefore, understanding the physiological impacts of global warming in relation to longevity of animals will become very crucial challenge to biologists of the present millennium.

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“…They can be utilized as therapeutic targets for diseases mainly related to protein misfolding. Protein fibrillation is responsible for several amyloidogenic disorders including diseases such as Alzheimer's, Parkinson's, mad cow, diabetes type II, cystic fibroisis, and dialysis related amyloidosis [58,59]. Though there have been several studies describing the effects of osmolytes on fibrillation/aggregation of proteins [60][61][62][63][64][65][66], quantitative understanding in terms of energetics of interaction has only recently been addressed Page 3 of 5 [67,68].…”

Section: Role In Prevention Of Aggregation/fibrillation Of Proteinmentioning

confidence: 99%

Biological Wonders of Osmolytes: The Need to Know More

Judy¹,

Kishore²

2016

Biochem Anal Biochem

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Nature has selected osmolytes to protect intracellular macromolecules against denaturing stress conditions. These molecules are accumulated in the intracellular environment at considerably high concentrations. In general, osmolytes are known to stabilize proteins. However, under certain conditions, their destabilizing properties have also been pointed out. A careful qualitative and quantitative understanding of the mechanism of action of osmolytes with proteins from native to different stages of aggregation/fibrillation is extremely important in rational drug design. This review highlights the importance of naturally occurring osmolytes in protein folding, stabilization, and prevention of fibrillation/aggregation related diseases among others. Continued efforts are required to get quantitative insights into osmolyte-protein interactions along with experimental evidences for the much claimed preferential exclusion/preferential hydration phenomenon of osmolyte action. Mechanistic insights into the disease associated roles of osmolytes needs special attention.

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Molecular and cellular aspects of protein misfolding and disease

Cited by 181 publications

References 276 publications

Misfolded proteins activate Factor XII in humans, leading to kallikrein formation without initiating coagulation

Misfolded proteins activate Factor XII in humans, leading to kallikrein formation without initiating coagulation

Longevity of animals under reactive oxygen species stress and disease susceptibility due to global warming

Biological Wonders of Osmolytes: The Need to Know More

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