Cellular strategies to cope with protein aggregation

2016 ◽  
Vol 60 (2) ◽  
pp. 153-161 ◽  
Author(s):  
Annika Scior ◽  
Katrin Juenemann ◽  
Janine Kirstein
Keyword(s):  
Protein Aggregation ◽  
Molecular Chaperones ◽  
Protein Aggregates ◽  
Misfolded Proteins ◽  
Protein Species ◽  
Intracellular Protein ◽  
Controlled Deposition ◽  
Control Protein

Nature has evolved several mechanisms to detoxify intracellular protein aggregates that arise upon proteotoxic challenges. These include the controlled deposition of misfolded proteins at distinct cellular sites, the protein disaggregation and refolding by molecular chaperones and/or degradation of misfolded and aggregated protein species by cellular clearance pathways. In this article, we discuss cellular the strategies of prokaroytes and eukaryotes to control protein aggregation.

scholarly journals Proteinaceous Infectious Behavior in Non-pathogenic Proteins Is Controlled by Molecular Chaperones

2002 ◽  
Vol 277 (51) ◽  
pp. 49422-49427 ◽  
Author(s):  
Anat Peres Ben-Zvi ◽  
Pierre Goloubinoff
Keyword(s):  
Heat Stress ◽  
Protein Aggregation ◽  
Molecular Chaperones ◽  
Polypeptide Chain ◽  
Protein Aggregates ◽  
Single Polypeptide Chain ◽  
Activity Measurements ◽  
Associated Proteins ◽  
External Stresses ◽  
Single Polypeptide

External stresses or mutations may cause labile proteins to lose their distinct native conformations and seek alternatively stable aggregated forms. Molecular chaperones that specifically act on protein aggregates were used here as a tool to address the biochemical nature of stable homo- and hetero-aggregates from non-pathogenic proteins formed by heat-stress. Confirmed by sedimentation and activity measurements, chaperones demonstrated that a single polypeptide chain can form different species of aggregates, depending on the denaturing conditions. Indicative of a cascade reaction, sub-stoichiometric amounts of one fast-aggregating protein strongly accelerated the conversion of another soluble, slow-aggregating protein into insoluble, chaperone-resistant aggregates. Chaperones strongly inhibited seed-induced protein aggregation, suggesting that they can prevent and cure proteinaceous infectious behavior in homo- and hetero-aggregates from common and disease-associated proteins in the cell.

scholarly journals Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates

2020 ◽  
Author(s):  
Paula García-Huerta ◽  
Paulina Troncoso-Escudero ◽  
Di Wu ◽  
Arun Thiruvalluvan ◽  
Marisol Cisternas ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Aggregation ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Aggregates ◽  
Insulin Like Growth Factor ◽  
Mutant Huntingtin ◽  
Intracellular Protein ◽  
Abnormal Protein ◽  
Disease Modifier

AbstractImpaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various models of neurodegeneration. To identify disease-modifier genes that may explain the neuroprotective effects of XBP1 deficiency, we performed gene expression profiling of brain cortex and striatum of these animals and uncovered insulin-like growth factor 2 (Igf2) as the major upregulated gene. Here we studied the impact of IGF2 signaling on protein aggregation in models of Huntington’s disease (HD) as proof-of-concept. Cell culture studies revealed that IGF2 treatment decreases the load of intracellular aggregates of mutant huntingtin and a polyglutamine peptide. These results were validated using induced pluripotent stem cells (iPSC)-derived medium spiny neurons from HD patients. The reduction in the levels of mutant huntingtin was associated with a decrease in the half-life of the intracellular protein. The decrease in the levels of abnormal protein aggregation triggered by IGF2 were independent of the activity of autophagy and the proteasome pathways, the two main routes for mutant huntingtin clearance. Conversely, IGF2 signaling enhanced the secretion of soluble mutant huntingtin species through exosomes and microvesicles involving changes in actin dynamics. Administration of IGF2 into the brain of HD mice using gene therapy led to a significant decrease in the levels of mutant huntingtin in three different animal models. Moreover, analysis of human post-mortem brain tissue, and blood samples from HD patients showed a reduction of IGF2 level. This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of abnormal protein aggregates.One sentence summaryIGF2 reduces the load of intracellular protein aggregates through the extracellular disposal of the mutant protein.

scholarly journals Intracellular Protein Aggregation Is a Proximal Trigger of Cardiomyocyte Autophagy

Circulation ◽  
2008 ◽  
Vol 117 (24) ◽  
pp. 3070-3078 ◽  
Author(s):  
Paul Tannous ◽  
Hongxin Zhu ◽  
Andriy Nemchenko ◽  
Jeff M. Berry ◽  
Janet L. Johnstone ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Intracellular Protein ◽  
Cardiomyocyte Autophagy

scholarly journals UXT chaperone prevents proteotoxicity by acting as an autophagy adaptor for p62-dependent aggrephagy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Min Ji Yoon ◽  
Boyoon Choi ◽  
Eun Jin Kim ◽  
Jiyeon Ohk ◽  
Chansik Yang ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Chaperones ◽  
Ectopic Expression ◽  
Protein Aggregates ◽  
Yeast Two Hybrid ◽  
Ubiquitinated Protein ◽  
Interacting Protein ◽  
Autophagy Pathway ◽  
Cooperative Relationship ◽  
Two Hybrid

Abstractp62/SQSTM1 is known to act as a key mediator in the selective autophagy of protein aggregates, or aggrephagy, by steering ubiquitinated protein aggregates towards the autophagy pathway. Here, we use a yeast two-hybrid screen to identify the prefoldin-like chaperone UXT as an interacting protein of p62. We show that UXT can bind to protein aggregates as well as the LB domain of p62, and, possibly by forming an oligomer, increase p62 clustering for its efficient targeting to protein aggregates, thereby promoting the formation of the p62 body and clearance of its cargo via autophagy. We also find that ectopic expression of human UXT delays SOD1(A4V)-induced degeneration of motor neurons in a Xenopus model system, and that specific disruption of the interaction between UXT and p62 suppresses UXT-mediated protection. Together, these results indicate that UXT functions as an autophagy adaptor of p62-dependent aggrephagy. Furthermore, our study illustrates a cooperative relationship between molecular chaperones and the aggrephagy machinery that efficiently removes misfolded protein aggregates.

scholarly journals Specificity in intracellular protein aggregation and inclusion body formation

2001 ◽  
Vol 98 (23) ◽  
pp. 13060-13065 ◽  
Author(s):  
R. S. Rajan ◽  
M. E. Illing ◽  
N. F. Bence ◽  
R. R. Kopito
Keyword(s):  
Protein Aggregation ◽  
Inclusion Body ◽  
Intracellular Protein ◽  
Body Formation ◽  
Inclusion Body Formation

scholarly journals Disaggregases, molecular chaperones that resolubilize protein aggregates

2015 ◽  
Vol 87 (2 suppl) ◽  
pp. 1273-1292 ◽  
Author(s):  
David Z. Mokry ◽  
Josielle Abrahão ◽  
Carlos H.I. Ramos
Keyword(s):  
Heat Shock ◽  
Molecular Chaperones ◽  
Protein Function ◽  
Protein Aggregates ◽  
Cell Physiology ◽  
Biological Processes ◽  
Loss Of Function ◽  
Prion Propagation ◽  
Shock Proteins

The process of folding is a seminal event in the life of a protein, as it is essential for proper protein function and therefore cell physiology. Inappropriate folding, or misfolding, can not only lead to loss of function, but also to the formation of protein aggregates, an insoluble association of polypeptides that harm cell physiology, either by themselves or in the process of formation. Several biological processes have evolved to prevent and eliminate the existence of non-functional and amyloidogenic aggregates, as they are associated with several human pathologies. Molecular chaperones and heat shock proteins are specialized in controlling the quality of the proteins in the cell, specifically by aiding proper folding, and dissolution and clearance of already formed protein aggregates. The latter is a function of disaggregases, mainly represented by the ClpB/Hsp104 subfamily of molecular chaperones, that are ubiquitous in all organisms but, surprisingly, have no orthologs in the cytosol of metazoan cells. This review aims to describe the characteristics of disaggregases and to discuss the function of yeast Hsp104, a disaggregase that is also involved in prion propagation and inheritance.

scholarly journals Heat Shock Protein 90 as Therapeutic Target for CVDs and Heart Ageing

2022 ◽  
Vol 23 (2) ◽  
pp. 649
Author(s):  
Siarhei A. Dabravolski ◽  
Vasily N. Sukhorukov ◽  
Vladislav A. Kalmykov ◽  
Nikolay A. Orekhov ◽  
Andrey V. Grechko ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Molecular Chaperones ◽  
Heat Shock Protein 90 ◽  
Misfolded Proteins ◽  
Heart Cells ◽  
Metabolic Demand ◽  
Heart Protection ◽  
High Metabolic Demand

Cardiovascular diseases (CVDs) are the leading cause of death globally, representing approximately 32% of all deaths worldwide. Molecular chaperones are involved in heart protection against stresses and age-mediated accumulation of toxic misfolded proteins by regulation of the protein synthesis/degradation balance and refolding of misfolded proteins, thus supporting the high metabolic demand of the heart cells. Heat shock protein 90 (HSP90) is one of the main cardioprotective chaperones, represented by cytosolic HSP90a and HSP90b, mitochondrial TRAP1 and ER-localised Grp94 isoforms. Currently, the main way to study the functional role of HSPs is the application of HSP inhibitors, which could have a different way of action. In this review, we discussed the recently investigated role of HSP90 proteins in cardioprotection, atherosclerosis, CVDs development and the involvements of HSP90 clients in the activation of different molecular pathways and signalling mechanisms, related to heart ageing.

scholarly journals Molecular chaperones cooperate with PIM1 protease in the degradation of misfolded proteins in mitochondria.

1994 ◽  
Vol 13 (21) ◽  
pp. 5135-5145 ◽  
Author(s):  
I. Wagner ◽  
H. Arlt ◽  
L. van Dyck ◽  
T. Langer ◽  
W. Neupert
Keyword(s):  
Molecular Chaperones ◽  
Misfolded Proteins

scholarly journals Keeping α-Synuclein at Bay: A More Active Role of Molecular Chaperones in Preventing Mitochondrial Interactions and Transition to Pathological States?

Life ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 289
Author(s):  
Emelie E. Aspholm ◽  
Irena Matečko-Burmann ◽  
Björn M. Burmann
Keyword(s):  
Molecular Chaperones ◽  
Mitochondrial Membrane ◽  
Structural Transition ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Protein Aggregates ◽  
Active Role ◽  
Proteolytic Processing ◽  
Membrane Disruption

The property of molecular chaperones to dissolve protein aggregates of Parkinson-related α-synuclein has been known for some time. Recent findings point to an even more active role of molecular chaperones preventing the transformation of α-synuclein into pathological states subsequently leading to the formation of Lewy bodies, intracellular inclusions containing protein aggregates as well as broken organelles found in the brains of Parkinson’s patients. In parallel, a short motif around Tyr39 was identified as being crucial for the aggregation of α-synuclein. Interestingly, this region is also one of the main segments in contact with a diverse pool of molecular chaperones. Further, it could be shown that the inhibition of the chaperone:α-synuclein interaction leads to a binding of α-synuclein to mitochondria, which could also be shown to lead to mitochondrial membrane disruption as well as the possible proteolytic processing of α-synuclein by mitochondrial proteases. Here, we will review the current knowledge on the role of molecular chaperones in the regulation of physiological functions as well as the direct consequences of impairing these interactions—i.e., leading to enhanced mitochondrial interaction and consequential mitochondrial breakage, which might mark the initial stages of the structural transition of α-synuclein towards its pathological states.

scholarly journals Molecular chaperones in targeting misfolded proteins for ubiquitin-dependent degradation

FEBS Journal ◽  
2012 ◽  
Vol 279 (4) ◽  
pp. 532-542 ◽  
Author(s):  
Franziska Kriegenburg ◽  
Lars Ellgaard ◽  
Rasmus Hartmann-Petersen
Keyword(s):  
Molecular Chaperones ◽  
Misfolded Proteins
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