Journal articles: 'Protein misfolding and aggregation'

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Murphy, Regina M., and Brent S. Kendrick. "Protein Misfolding and Aggregation." Biotechnology Progress 23, no. 3 (September 5, 2008): 548–52. http://dx.doi.org/10.1021/bp060374h.

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Cuervo, Ana Maria, Esther S. P. Wong, and Marta Martinez-Vicente. "Protein degradation, aggregation, and misfolding." Movement Disorders 25, S1 (2010): S49—S54. http://dx.doi.org/10.1002/mds.22718.

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Popiel, H. Akiko, James R. Burke, Warren J. Strittmatter, Shinya Oishi, Nobutaka Fujii, Toshihide Takeuchi, Tatsushi Toda, Keiji Wada, and Yoshitaka Nagai. "The Aggregation Inhibitor Peptide QBP1 as a Therapeutic Molecule for the Polyglutamine Neurodegenerative Diseases." Journal of Amino Acids 2011 (June 30, 2011): 1–10. http://dx.doi.org/10.4061/2011/265084.

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Misfolding and abnormal aggregation of proteins in the brain are implicated in the pathogenesis of various neurodegenerative diseases including Alzheimer's, Parkinson's, and the polyglutamine (polyQ) diseases. In the polyQ diseases, an abnormally expanded polyQ stretch triggers misfolding and aggregation of the disease-causing proteins, eventually resulting in neurodegeneration. In this paper, we introduce our therapeutic strategy against the polyQ diseases using polyQ binding peptide 1 (QBP1), a peptide that we identified by phage display screening. We showed that QBP1 specifically binds to the expanded polyQ stretch and inhibits its misfolding and aggregation, resulting in suppression of neurodegeneration in cell culture and animal models of the polyQ diseases. We further demonstrated the potential of protein transduction domains (PTDs) for in vivo delivery of QBP1. We hope that in the near future, chemical analogues of aggregation inhibitor peptides including QBP1 will be developed against protein misfolding-associated neurodegenerative diseases.

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Ajmal, Mohammad Rehan. "Protein Misfolding and Aggregation in Proteinopathies: Causes, Mechanism and Cellular Response." Diseases 11, no. 1 (February 9, 2023): 30. http://dx.doi.org/10.3390/diseases11010030.

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Proteins are central to life functions. Alterations in the structure of proteins are reflected in their function. Misfolded proteins and their aggregates present a significant risk to the cell. Cells have a diverse but integrated network of protection mechanisms. Streams of misfolded proteins that cells are continuously exposed to must be continually monitored by an elaborated network of molecular chaperones and protein degradation factors to control and contain protein misfolding problems. Aggregation inhibition properties of small molecules such as polyphenols are important as they possess other beneficial properties such as antioxidative, anti-inflammatory, and pro-autophagic properties and help neuroprotection. A candidate with such desired features is important for any possible treatment development for protein aggregation diseases. There is a need to study the protein misfolding phenomenon so that we can treat some of the worst kinds of human ailments related to protein misfolding and aggregation.

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Wang, Chen-Yu, Hui-Ching Lin, Yi-Ping Song, Yu-Ting Hsu, Shu-Yu Lin, Pei-Chien Hsu, Chun-Hua Lin, et al. "Protein Kinase C-Dependent Growth-Associated Protein 43 Phosphorylation Regulates Gephyrin Aggregation at Developing GABAergic Synapses." Molecular and Cellular Biology 35, no. 10 (March 9, 2015): 1712–26. http://dx.doi.org/10.1128/mcb.01332-14.

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Growth-associated protein 43 (GAP43) is known to regulate axon growth, but whether it also plays a role in synaptogenesis remains unclear. Here, we found that GAP43 regulates the aggregation of gephyrin, a pivotal protein for clustering postsynaptic GABAAreceptors (GABAARs), in developing cortical neurons. Pharmacological blockade of either protein kinase C (PKC) or neuronal activity increased both GAP43-gephyrin association and gephyrin misfolding-induced aggregation, suggesting the importance of PKC-dependent regulation of GABAergic synapses. Furthermore, we found that PKC phosphorylation-resistant GAP43S41A, but not PKC phosphorylation-mimicking GAP43S41D, interacted with cytosolic gephyrin to trigger gephyrin misfolding and its sequestration into aggresomes. In contrast, GAP43S41D, but not GAP43S41A, inhibited the physiological aggregation/clustering of gephyrin, reduced surface GABAARs under physiological conditions, and attenuated gephyrin misfolding under transient oxygen-glucose deprivation (tOGD) that mimics pathological neonatal hypoxia. Calcineurin-mediated GAP43 dephosphorylation that accompanied tOGD also led to GAP43-gephyrin association and gephyrin misfolding. Thus, PKC-dependent phosphorylation of GAP43 plays a critical role in regulating postsynaptic gephyrin aggregation in developing GABAergic synapses.

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Cuanalo-Contreras, Karina, Abhisek Mukherjee, and Claudio Soto. "Role of Protein Misfolding and Proteostasis Deficiency in Protein Misfolding Diseases and Aging." International Journal of Cell Biology 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/638083.

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The misfolding, aggregation, and tissue accumulation of proteins are common events in diverse chronic diseases, known as protein misfolding disorders. Many of these diseases are associated with aging, but the mechanism for this connection is unknown. Recent evidence has shown that the formation and accumulation of protein aggregates may be a process frequently occurring during normal aging, but it is unknown whether protein misfolding is a cause or a consequence of aging. To combat the formation of these misfolded aggregates cells have developed complex and complementary pathways aiming to maintain protein homeostasis. These protective pathways include the unfolded protein response, the ubiquitin proteasome system, autophagy, and the encapsulation of damaged proteins in aggresomes. In this paper we review the current knowledge on the role of protein misfolding in disease and aging as well as the implication of deficiencies in the proteostasis cellular pathways in these processes. It is likely that further understanding of the mechanisms involved in protein misfolding and the natural defense pathways may lead to novel strategies for treatment of age-dependent protein misfolding disorders and perhaps aging itself.

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Lu, Rui-Chun, Meng-Shan Tan, Hao Wang, An-Mu Xie, Jin-Tai Yu, and Lan Tan. "Heat Shock Protein 70 in Alzheimer’s Disease." BioMed Research International 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/435203.

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Alzheimer’s disease (AD) is the most common neurodegenerative disease that caused dementia which has no effective treatment. Growing evidence has demonstrated that AD is a “protein misfolding disorder” that exhibits common features of misfolded, aggregation-prone proteins and selective cell loss in the mature nervous system. Heat shock protein 70 (HSP70) attracts extensive attention worldwide, because it plays a crucial role in preventing protein misfolding and inhibiting aggregation and represents a class of proteins potentially involved in AD pathogenesis. Numerous studies have indicated that HSP70 could suppress the progression of AD within vitroandin vivoexperiments. Thus, targeting HSP70 and the related compounds might represent a promising strategy for the treatment of AD.

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Tan, Jeanne M. M., Esther S. P. Wong, and Kah-Leong Lim. "Protein Misfolding and Aggregation in Parkinson's Disease." Antioxidants & Redox Signaling 11, no. 9 (September 2009): 2119–34. http://dx.doi.org/10.1089/ars.2009.2490.

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Dobson, Christopher M. "Principles of protein folding, misfolding and aggregation." Seminars in Cell & Developmental Biology 15, no. 1 (February 2004): 3–16. http://dx.doi.org/10.1016/j.semcdb.2003.12.008.

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Lyubchenko, Yuri. "Nanoprobing immunoassay for protein misfolding and aggregation." Nanomedicine: Nanotechnology, Biology and Medicine 3, no. 4 (December 2007): 342. http://dx.doi.org/10.1016/j.nano.2007.10.033.

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Pastore, Annalisa, and Pierandrea Temussi. "Protein aggregation and misfolding: good or evil?" Journal of Physics: Condensed Matter 24, no. 24 (May 18, 2012): 244101. http://dx.doi.org/10.1088/0953-8984/24/24/244101.

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Yu, Hao, Derek R. Dee, Xia Liu, Angela M. Brigley, Iveta Sosova, and Michael T. Woodside. "Protein misfolding occurs by slow diffusion across multiple barriers in a rough energy landscape." Proceedings of the National Academy of Sciences 112, no. 27 (June 24, 2015): 8308–13. http://dx.doi.org/10.1073/pnas.1419197112.

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The timescale for the microscopic dynamics of proteins during conformational transitions is set by the intrachain diffusion coefficient, D. Despite the central role of protein misfolding and aggregation in many diseases, it has proven challenging to measure D for these processes because of their heterogeneity. We used single-molecule force spectroscopy to overcome these challenges and determine D for misfolding of the prion protein PrP. Observing directly the misfolding of individual dimers into minimal aggregates, we reconstructed the energy landscape governing nonnative structure formation. Remarkably, rather than displaying multiple pathways, as typically expected for aggregation, PrP dimers were funneled into a thermodynamically stable misfolded state along a single pathway containing several intermediates, one of which blocked native folding. Using Kramers’ rate theory, D was found to be 1,000-fold slower for misfolding than for native folding, reflecting local roughening of the misfolding landscape, likely due to increased internal friction. The slow diffusion also led to much longer transit times for barrier crossing, allowing transition paths to be observed directly for the first time to our knowledge. These results open a new window onto the microscopic mechanisms governing protein misfolding.

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Padilla-Godínez, Francisco J., Rodrigo Ramos-Acevedo, Hilda Angélica Martínez-Becerril, Luis D. Bernal-Conde, Jerónimo F. Garrido-Figueroa, Marcia Hiriart, Adriana Hernández-López, Rubén Argüero-Sánchez, Francesco Callea, and Magdalena Guerra-Crespo. "Protein Misfolding and Aggregation: The Relatedness between Parkinson’s Disease and Hepatic Endoplasmic Reticulum Storage Disorders." International Journal of Molecular Sciences 22, no. 22 (November 18, 2021): 12467. http://dx.doi.org/10.3390/ijms222212467.

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Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several disorders, including neurodegenerative diseases, such as Parkinson’s disease (PD), and endoplasmic reticulum storage disorders (ERSDs), like alpha-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Given the shared pathophysiological mechanisms involved in such conditions, it is necessary to deepen our understanding of the basic principles of misfolding and aggregation akin to these diseases which, although heterogeneous in symptomatology, present similarities that could lead to potential mutual treatments. Here, we review: (i) the pathological bases leading to misfolding and aggregation of proteins involved in PD, AATD, and HHHS: alpha-synuclein, alpha-1-antitrypsin, and fibrinogen, respectively, (ii) the evidence linking each protein aggregation to the stress mechanisms occurring in the endoplasmic reticulum (ER) of each pathology, (iii) a comparison of the mechanisms related to dysfunction of proteostasis and regulation of homeostasis between the diseases (such as the unfolded protein response and/or autophagy), (iv) and clinical perspectives regarding possible common treatments focused on improving the defensive responses to protein aggregation for diseases as different as PD, and ERSDs.

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Kim, Heejung, and Kevin Strange. "Changes in translation rate modulate stress-induced damage of diverse proteins." American Journal of Physiology-Cell Physiology 305, no. 12 (December 15, 2013): C1257—C1264. http://dx.doi.org/10.1152/ajpcell.00176.2013.

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Proteostasis is the maintenance of the proper function of cellular proteins. Hypertonic stress disrupts proteostasis and causes rapid and widespread protein aggregation and misfolding in the nematode Caenorhabditis elegans. Optimal survival in hypertonic environments requires degradation of damaged proteins. Inhibition of protein synthesis occurs in response to diverse environmental stressors and may function in part to minimize stress-induced protein damage. We recently tested this idea directly and demonstrated that translation inhibition by acute exposure to cycloheximide suppresses hypertonicity-induced aggregation of polyglutamine::YFP (Q35::YFP) in body wall muscle cells. In this article, we further characterized the relationship between protein synthesis and hypertonic stress-induced protein damage. We demonstrate that inhibition of translation reduces hypertonic stress-induced formation and growth of Q35::YFP, Q44::YFP, and α-synuclein aggregates; misfolding of paramyosin and ras GTPase; and aggregation of multiple endogenous proteins expressed in diverse cell types. Activation of general control nonderepressible-2 (GCN-2) kinase signaling during hypertonic stress inhibits protein synthesis via phosphorylation of eukaryotic initiation factor-2α (eIF-2α). Inhibition of GCN-2 activation prevents the reduction in translation rate and greatly exacerbates the formation and growth of Q35::YFP aggregates and the aggregation of endogenous proteins. The current studies together with our previous work provide the first direct demonstration that hypertonic stress-induced reduction in protein synthesis minimizes protein aggregation and misfolding. Reduction in translation rate also serves as a signal that activates osmoprotective gene expression. The cellular proteostasis network thus plays a critical role in minimizing hypertonic stress-induced protein damage, in degrading stress-damaged proteins, and in cellular osmosensing and signaling.

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Choi, Seong Il, and Baik L. Seong. "A Conceptual Framework for Integrating Cellular Protein Folding, Misfolding and Aggregation." Life 11, no. 7 (June 24, 2021): 605. http://dx.doi.org/10.3390/life11070605.

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How proteins properly fold and maintain solubility at the risk of misfolding and aggregation in the cellular environments still remains largely unknown. Aggregation has been traditionally treated as a consequence of protein folding (or misfolding). Notably, however, aggregation can be generally inhibited by affecting the intermolecular interactions leading to aggregation, independently of protein folding and conformation. We here point out that rigorous distinction between protein folding and aggregation as two independent processes is necessary to reconcile and underlie all observations regarding the combined cellular protein folding and aggregation. So far, the direct attractive interactions (e.g., hydrophobic interactions) between cellular macromolecules including chaperones and interacting polypeptides have been widely believed to mainly stabilize polypeptides against aggregation. However, the intermolecular repulsions by large excluded volume and surface charges of cellular macromolecules can play a key role in stabilizing their physically connected polypeptides against aggregation, irrespective of the connection types and induced conformational changes, underlying the generic intrinsic chaperone activity of cellular macromolecules. Such rigorous distinction and intermolecular repulsive force-driven aggregation inhibition by cellular macromolecules could give new insights into understanding the complex cellular protein landscapes that remain uncharted.

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Saunders, H. M., and S. P. Bottomley. "Multi-domain misfolding: understanding the aggregation pathway of polyglutamine proteins." Protein Engineering Design and Selection 22, no. 8 (July 9, 2009): 447–51. http://dx.doi.org/10.1093/protein/gzp033.

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Blancas-Mejia, Luis M., Pinaki Misra, Christopher J. Dick, Shawna A. Cooper, Keely R. Redhage, Michael R. Bergman, Torri L. Jordan, Khansaa Maar, and Marina Ramirez-Alvarado. "Immunoglobulin light chain amyloid aggregation." Chemical Communications 54, no. 76 (2018): 10664–74. http://dx.doi.org/10.1039/c8cc04396e.

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18

Shorter, James. "Engineering therapeutic protein disaggregases." Molecular Biology of the Cell 27, no. 10 (May 15, 2016): 1556–60. http://dx.doi.org/10.1091/mbc.e15-10-0693.

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Therapeutic agents are urgently required to cure several common and fatal neurodegenerative disorders caused by protein misfolding and aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD). Protein disaggregases that reverse protein misfolding and restore proteins to native structure, function, and localization could mitigate neurodegeneration by simultaneously reversing 1) any toxic gain of function of the misfolded form and 2) any loss of function due to misfolding. Potentiated variants of Hsp104, a hexameric AAA+ ATPase and protein disaggregase from yeast, have been engineered to robustly disaggregate misfolded proteins connected with ALS (e.g., TDP-43 and FUS) and PD (e.g., α-synuclein). However, Hsp104 has no metazoan homologue. Metazoa possess protein disaggregase systems distinct from Hsp104, including Hsp110, Hsp70, and Hsp40, as well as HtrA1, which might be harnessed to reverse deleterious protein misfolding. Nevertheless, vicissitudes of aging, environment, or genetics conspire to negate these disaggregase systems in neurodegenerative disease. Thus, engineering potentiated human protein disaggregases or isolating small-molecule enhancers of their activity could yield transformative therapeutics for ALS, PD, and AD.

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Webster, Jack M., April L. Darling, Taylor A. Sanders, Danielle M. Blazier, Yamile Vidal-Aguiar, David Beaulieu-Abdelahad, Drew G. Plemmons, et al. "Hsp22 with an N-Terminal Domain Truncation Mediates a Reduction in Tau Protein Levels." International Journal of Molecular Sciences 21, no. 15 (July 30, 2020): 5442. http://dx.doi.org/10.3390/ijms21155442.

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Misfolding, aggregation and accumulation of proteins are toxic elements in the progression of a broad range of neurodegenerative diseases. Molecular chaperones enable a cellular defense by reducing or compartmentalizing these insults. Small heat shock proteins (sHsps) engage proteins early in the process of misfolding and can facilitate their proper folding or refolding, sequestration, or clearance. Here, we evaluate the effects of the sHsp Hsp22, as well as a pseudophosphorylated mutant and an N-terminal domain deletion (NTDΔ) variant on tau aggregation in vitro and tau accumulation and aggregation in cultured cells. Hsp22 wild-type (WT) protein had a significant inhibitory effect on heparin-induced aggregation in vitro and the pseudophosphorylated mutant Hsp22 demonstrated a similar effect. When co-expressed in a cell culture model with tau, these Hsp22 constructs significantly reduced soluble tau protein levels when transfected at a high ratio relative to tau. However, the Hsp22 NTDΔ protein drastically reduced the soluble protein expression levels of both tau WT and tau P301L/S320F even at lower transfection ratios, which resulted in a correlative reduction of the triton-insoluble tau P301L/S320F aggregates.

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Mossuto, Maria Francesca. "Disulfide Bonding in Neurodegenerative Misfolding Diseases." International Journal of Cell Biology 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/318319.

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In recent years an increasing number of neurodegenerative diseases has been linked to the misfolding of a specific protein and its subsequent accumulation into aggregated species, often toxic to the cell. Of all the factors that affect the behavior of these proteins, disulfide bonds are likely to be important, being very conserved in protein sequences and being the enzymes devoted to their formation among the most conserved machineries in mammals. Their crucial role in the folding and in the function of a big fraction of the human proteome is well established. The role of disulfide bonding in preventing and managing protein misfolding and aggregation is currently under investigation. New insights into their involvement in neurodegenerative diseases, their effect on the process of protein misfolding and aggregation, and into the role of the cellular machineries devoted to disulfide bond formation in neurodegenerative diseases are emerging. These studies mark a step forward in the comprehension of the biological base of neurodegenerative disorders and highlight the numerous questions that still remain open.

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Bigi, Alessandra, Eva Lombardo, Roberta Cascella, and Cristina Cecchi. "The Toxicity of Protein Aggregates: New Insights into the Mechanisms." International Journal of Molecular Sciences 24, no. 9 (April 28, 2023): 7974. http://dx.doi.org/10.3390/ijms24097974.

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Sanz-Hernández, Máximo, Joseph D. Barritt, Jens Sobek, Simone Hornemann, Adriano Aguzzi, and Alfonso De Simone. "Mechanism of misfolding of the human prion protein revealed by a pathological mutation." Proceedings of the National Academy of Sciences 118, no. 12 (March 17, 2021): e2019631118. http://dx.doi.org/10.1073/pnas.2019631118.

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The misfolding and aggregation of the human prion protein (PrP) is associated with transmissible spongiform encephalopathies (TSEs). Intermediate conformations forming during the conversion of the cellular form of PrP into its pathological scrapie conformation are key drivers of the misfolding process. Here, we analyzed the properties of the C-terminal domain of the human PrP (huPrP) and its T183A variant, which is associated with familial forms of TSEs. We show that the mutation significantly enhances the aggregation propensity of huPrP, such as to uniquely induce amyloid formation under physiological conditions by the sole C-terminal domain of the protein. Using NMR spectroscopy, biophysics, and metadynamics simulations, we identified the structural characteristics of the misfolded intermediate promoting the aggregation of T183A huPrP and the nature of the interactions that prevent this species to be populated in the wild-type protein. In support of these conclusions, POM antibodies targeting the regions that promote PrP misfolding were shown to potently suppress the aggregation of this amyloidogenic mutant.

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Li, Haoqian, Richard Lantz, and Deguo Du. "Vibrational Approach to the Dynamics and Structure of Protein Amyloids." Molecules 24, no. 1 (January 6, 2019): 186. http://dx.doi.org/10.3390/molecules24010186.

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Amyloid diseases, including neurodegenerative diseases such as Alzheimer’s and Parkinson’s, are linked to a poorly understood progression of protein misfolding and aggregation events that culminate in tissue-selective deposition and human pathology. Elucidation of the mechanistic details of protein aggregation and the structural features of the aggregates is critical for a comprehensive understanding of the mechanisms of protein oligomerization and fibrillization. Vibrational spectroscopies, such as Fourier transform infrared (FTIR) and Raman, are powerful tools that are sensitive to the secondary structure of proteins and have been widely used to investigate protein misfolding and aggregation. We address the application of the vibrational approaches in recent studies of conformational dynamics and structural characteristics of protein oligomers and amyloid fibrils. In particular, introduction of isotope labelled carbonyl into a peptide backbone, and incorporation of the extrinsic unnatural amino acids with vibrational moieties on the side chain, have greatly expanded the ability of vibrational spectroscopy to obtain site-specific structural and dynamic information. The applications of these methods in recent studies of protein aggregation are also reviewed.

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Dave, Kapil, Andrei G. Gasic, Margaret S. Cheung, and M. Gruebele. "Competition of individual domain folding with inter-domain interaction in WW domain engineered repeat proteins." Physical Chemistry Chemical Physics 21, no. 44 (2019): 24393–405. http://dx.doi.org/10.1039/c8cp07775d.

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Biocca, Silvia, and Alessio Cardinale. "Combating Protein Misfolding and Aggregation by Intracellular Antibodies." Current Molecular Medicine 8, no. 1 (February 1, 2008): 2–11. http://dx.doi.org/10.2174/156652408783565595.

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Tuite, Mick F., and Ronald Melki. "Protein Misfolding and Aggregation in Ageing and Disease." Prion 1, no. 2 (April 2007): 116–20. http://dx.doi.org/10.4161/pri.1.2.4651.

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Sami, Neha, Safikur Rahman, Vijay Kumar, Sobia Zaidi, Asimul Islam, Sher Ali, Faizan Ahmad, and Md Imtaiyaz Hassan. "Protein aggregation, misfolding and consequential human neurodegenerative diseases." International Journal of Neuroscience 127, no. 11 (February 8, 2017): 1047–57. http://dx.doi.org/10.1080/00207454.2017.1286339.

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Xu, Shaohua. "Aggregation drives “misfolding” in protein amyloid fiber formation." Amyloid 14, no. 2 (January 1, 2007): 119–31. http://dx.doi.org/10.1080/13506120701260059.

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Chaturvedi, Sumit Kumar, Mohammad Khursheed Siddiqi, Parvez Alam, and Rizwan Hasan Khan. "Protein misfolding and aggregation: Mechanism, factors and detection." Process Biochemistry 51, no. 9 (September 2016): 1183–92. http://dx.doi.org/10.1016/j.procbio.2016.05.015.

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Hipp, Mark S., Sae-Hun Park, and F. Ulrich Hartl. "Proteostasis impairment in protein-misfolding and -aggregation diseases." Trends in Cell Biology 24, no. 9 (September 2014): 506–14. http://dx.doi.org/10.1016/j.tcb.2014.05.003.

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Luo, Tianfei, Yujung Park, Xin Sun, Chunli Liu, and Bingren Hu. "Protein Misfolding, Aggregation, and Autophagy After Brain Ischemia." Translational Stroke Research 4, no. 6 (November 9, 2013): 581–88. http://dx.doi.org/10.1007/s12975-013-0299-5.

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Kushwah, Neetu, Vishal Jain, and Dhananjay Yadav. "Osmolytes: A Possible Therapeutic Molecule for Ameliorating the Neurodegeneration Caused by Protein Misfolding and Aggregation." Biomolecules 10, no. 1 (January 13, 2020): 132. http://dx.doi.org/10.3390/biom10010132.

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Most of the neurological disorders in the brain are caused by the abnormal buildup of misfolded or aggregated proteins. Osmolytes are low molecular weight organic molecules usually built up in tissues at a quite high amount during stress or any pathological condition. These molecules help in providing stability to the aggregated proteins and protect these proteins from misfolding. Alzheimer’s disease (AD) is the uttermost universal neurological disorder that can be described by the deposition of neurofibrillary tangles, aggregated/misfolded protein produced by the amyloid β-protein (Aβ). Osmolytes provide stability to the folded, functional form of a protein and alter the folding balance away from aggregation and/or degradation of the protein. Moreover, they are identified as chemical chaperones. Brain osmolytes enhance the pace of Aβ aggregation, combine with the nearby water molecules more promptly, and avert the aggregation/misfolding of proteins by providing stability to them. Therefore, osmolytes can be employed as therapeutic targets and may assist in potential drug design for many neurodegenerative and other diseases.

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Puormand, Seyed Mahmoud, Arezou Ghahghaei, Jafar Valizadeh, and Shahrzad Nazari. "Protective Ability of Perovskia abrotanoides Karel Root Extract on the Aggregation of Protein In Vitro." Natural Products Journal 10, no. 2 (March 24, 2020): 113–21. http://dx.doi.org/10.2174/2210315509666190425125312.

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Background: Protein misfolding can lead to aggregation and these protein aggregates are a fundamental cause of many neurodegenerative disorders such as Alzheimer's, Parkinson's, Huntington's, Prion disease and amyotrophic lateral sclerosis. In recent years, a wide variety of natural compounds have been investigated as protein aggregation inhibitors. Many investigations have reported the therapeutic effects of botanicals constituents and their derivatives in neurodegenerative diseases. Objective: In this study, we examined the effect of Perovskia abrotanoides Karel (P. abrotanoides) root extract on the 1,4-dithiothreitol (DTT)-induced aggregation of proteins. Methods: The anti-aggregation ability of P. abrotanoides root extract was studied using visible absorption spectroscopy (light scattering), fluorescence spectroscopy, and circular dichroism (CD) spectroscopy. Results: The protective effect of P. abrotanoides root extract was varied in the three different-sized proteins (insulin, α-lactalbumin, and ovotransferrin). Conclusion: The results showed that P. abrotanoides root extract was able to inhibit protein aggregations in a concentration-dependent manner due to the interaction of P. abrotanoides root extract with hydrophobic area of proteins.

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Lasagna-Reeves, Cristian A., Audra L. Clos, Terumi Midoro-Hiriuti, Randall M. Goldblum, George R. Jackson, and Rakez Kayed. "Inhaled Insulin Forms Toxic Pulmonary Amyloid Aggregates." Endocrinology 151, no. 10 (August 4, 2010): 4717–24. http://dx.doi.org/10.1210/en.2010-0457.

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It is well known that interfaces, such as polar-nonpolar or liquid-air, play a key role in triggering protein aggregation in vitro, in particular the aggregation of peptides and proteins with the predisposition of misfolding and aggregation. Here we show that the interface present in the lungs predisposes the lungs to form aggregation of inhaled insulin. Insulin inhalers were introduced, and a large number of diabetic patients have used them. Although inhalers were safe and effective, decreases in pulmonary capacity have been reported in response to inhaled insulin. We hypothesize that the lung air-tissue interface provides a template for the aggregation of inhaled insulin. Our studies were designed to investigate the harmful potential that inhaled insulin has in pulmonary tissue in vivo, through an amyloid formation mechanism. Our data demonstrate that inhaled insulin rapidly forms amyloid in the lungs causing a significant reduction in pulmonary air flow. Our studies exemplify the importance that interfaces play in protein aggregation in vivo, illustrating the potential aggregation of inhaled proteins and the formation of amyloid deposits in the lungs. These insulin deposits resemble the amyloid structures implicated in protein misfolding disorders, such as Alzheimer’s and Parkinson’s diseases, and could as well be deleterious in nature.

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Heumüller, Stefanie-Elisabeth, and Ina Maja Vorberg. "Möglicher Einfluss von Viren auf die Ausbreitung von Proteinaggregaten." BIOspektrum 28, no. 2 (March 2022): 162–64. http://dx.doi.org/10.1007/s12268-022-1730-9.

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AbstractNeurodegenerative diseases are associated with misfolding of proteins into highly-ordered amyloid fibrils. These protein aggregates can be transmitted to other cells in which they induce aggregation of proteins of the same kind. Mechanisms of intercellular transfer include direct cell contact or transfer of aggregates within extracellular vesicles. Recent research suggests that viral proteins can increase the intercellular spreading of protein aggregation by promoting the required membrane interactions.

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Rochet, Jean-Christophe. "Novel therapeutic strategies for the treatment of protein-misfolding diseases." Expert Reviews in Molecular Medicine 9, no. 17 (June 2007): 1–34. http://dx.doi.org/10.1017/s1462399407000385.

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Most proteins in the cell adopt a compact, globular fold that determines their stability and function. Partial protein unfolding under conditions of cellular stress results in the exposure of hydrophobic regions normally buried in the interior of the native structure. Interactions involving the exposed hydrophobic surfaces of misfolded protein conformers lead to the formation of toxic aggregates, including oligomers, protofibrils and amyloid fibrils. A significant number of human disorders (e.g. Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and type II diabetes) are characterised by protein misfolding and aggregation. Over the past five years, outstanding progress has been made in the development of therapeutic strategies targeting these diseases. Three promising approaches include: (1) inhibiting protein aggregation with peptides or small molecules identified via structure-based drug design or high-throughput screening; (2) interfering with post-translational modifications that stimulate protein misfolding and aggregation; and (3) upregulating molecular chaperones or aggregate-clearance mechanisms. Ultimately, drug combinations that capitalise on more than one therapeutic strategy will constitute the most effective treatment for patients with these devastating illnesses.

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Cariulo, Cristina, Lucia Azzollini, Margherita Verani, Paola Martufi, Roberto Boggio, Anass Chiki, Sean M. Deguire, et al. "Phosphorylation of huntingtin at residue T3 is decreased in Huntington’s disease and modulates mutant huntingtin protein conformation." Proceedings of the National Academy of Sciences 114, no. 50 (November 21, 2017): E10809—E10818. http://dx.doi.org/10.1073/pnas.1705372114.

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Posttranslational modifications can have profound effects on the biological and biophysical properties of proteins associated with misfolding and aggregation. However, their detection and quantification in clinical samples and an understanding of the mechanisms underlying the pathological properties of misfolding- and aggregation-prone proteins remain a challenge for diagnostics and therapeutics development. We have applied an ultrasensitive immunoassay platform to develop and validate a quantitative assay for detecting a posttranslational modification (phosphorylation at residue T3) of a protein associated with polyglutamine repeat expansion, namely Huntingtin, and characterized its presence in a variety of preclinical and clinical samples. We find that T3 phosphorylation is greatly reduced in samples from Huntington’s disease models and in Huntington’s disease patients, and we provide evidence that bona-fide T3 phosphorylation alters Huntingtin exon 1 protein conformation and aggregation properties. These findings have significant implications for both mechanisms of disease pathogenesis and the development of therapeutics and diagnostics for Huntington’s disease.

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Sawyer, Elizabeth B., and Sarah Perrett. "The many faces of amyloid: Protein misfolding: failure or function?" Biochemist 33, no. 5 (October 1, 2011): 6–9. http://dx.doi.org/10.1042/bio03305006.

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The ability of proteins to recognize, bind and manipulate a wide range of other molecules lies at the heart of virtually every cellular process. In order to achieve this, proteins must fold into a precise three-dimensional structure. A failure to achieve this structure, and the associated loss of protein stability and function, results in diseases such as muscular dystrophy and cystic fibrosis. In addition, the misfolding and aggregation of proteins to form fibrillar species is associated with the progression of amyloid diseases such as Alzheimer's and Huntington's and prion diseases including Creutzfeldt– Jakob disease and bovine spongiform encephalopathy (BSE, or ‘mad cow disease’). In this article, we consider advances in the study of protein folding and misfolding and their relevance to biological function. We also explore the issue of protein ‘misfolding’ to form functional aggregated structures, such as the mode of epigenetic inheritance mediated by fungal prions and the formation of amyloid fibrils with positive biological functions in bacteria.

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Chien, Vita, Jacqueline F. Aitken, Shaoping Zhang, Christina M. Buchanan, Anthony Hickey, Thomas Brittain, Garth J. S. Cooper, and Kerry M. Loomes. "The chaperone proteins HSP70, HSP40/DnaJ and GRP78/BiP suppress misfolding and formation of β-sheet-containing aggregates by human amylin: a potential role for defective chaperone biology in Type 2 diabetes." Biochemical Journal 432, no. 1 (October 25, 2010): 113–21. http://dx.doi.org/10.1042/bj20100434.

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Misfolding of the islet β-cell peptide hA (human amylin) into β-sheet-containing oligomers is linked to β-cell apoptosis and the pathogenesis of T2DM (Type 2 diabetes mellitus). In the present study, we have investigated the possible effects on hA misfolding of the chaperones HSP (heat-shock protein) 70, GRP78/BiP (glucose-regulated protein of 78 kDa/immunoglobulin heavy-chain-binding protein) and HSP40/DnaJ. We demonstrate that hA underwent spontaneous time-dependent β-sheet formation and aggregation by thioflavin-T fluorescence in solution, whereas rA (rat amylin) did not. HSP70, GRP78/BiP and HSP40/DnaJ each independently suppressed hA misfolding. Maximal molar protein/hA ratios at which chaperone activity was detected were 1:200 (HSP70, HSP40/DnaJ and GRP78/BiP). By contrast, none of the chaperones modified the secondary structure of rA. hA, but not rA, was co-precipitated independently with HSP70 and GRP78/BiP by anti-amylin antibodies. As these effects occur at molar ratios consistent with chaperone binding to relatively rare misfolded hA species, we conclude that HSP70 and GRP78/BiP can detect and bind misfolded hA oligomers, thereby effectively protecting hA against bulk misfolding and irreversible aggregation. Defective β-cell chaperone biology could contribute to hA misfolding and initiation of apoptosis in T2DM.

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Carija, Pinheiro, Iglesias, and Ventura. "Computational Assessment of Bacterial Protein Structures Indicates a Selection Against Aggregation." Cells 8, no. 8 (August 8, 2019): 856. http://dx.doi.org/10.3390/cells8080856.

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The aggregation of proteins compromises cell fitness, either because it titrates functional proteins into non-productive inclusions or because it results in the formation of toxic assemblies. Accordingly, computational proteome-wide analyses suggest that prevention of aggregation upon misfolding plays a key role in sequence evolution. Most proteins spend their lifetimes in a folded state; therefore, it is conceivable that, in addition to sequences, protein structures would have also evolved to minimize the risk of aggregation in their natural environments. By exploiting the AGGRESCAN3D structure-based approach to predict the aggregation propensity of >600 Escherichia coli proteins, we show that the structural aggregation propensity of globular proteins is connected with their abundance, length, essentiality, subcellular location and quaternary structure. These data suggest that the avoidance of protein aggregation has contributed to shape the structural properties of proteins in bacterial cells.

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Trepte, Philipp, Nadine Strempel, and Erich E. Wanker. "Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures." Essays in Biochemistry 56 (August 18, 2014): 167–80. http://dx.doi.org/10.1042/bse0560167.

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PolyQ (polyglutamine) diseases such as HD (Huntington's disease) or SCA1 (spinocerebellar ataxia type 1) are neurodegenerative disorders caused by abnormally elongated polyQ tracts in human proteins. PolyQ expansions promote misfolding and aggregation of disease-causing proteins, leading to the appearance of nuclear and cytoplasmic inclusion bodies in patient neurons. Several lines of experimental evidence indicate that this process is critical for disease pathogenesis. However, the molecular mechanisms underlying spontaneous polyQ-containing aggregate formation and the perturbation of neuronal processes are still largely unclear. The present chapter reviews the current literature regarding misfolding and aggregation of polyQ-containing disease proteins. We specifically focus on studies that have investigated the amyloidogenesis of polyQ-containing HTTex1 (huntingtin exon 1) fragments. These protein fragments are disease-relevant and play a critical role in HD pathogenesis. We outline potential mechanisms behind mutant HTTex1 aggregation and toxicity, as well as proteins and small molecules that can modify HTTex1 amyloidogenesis in vitro and in vivo. The potential implications of such studies for the development of novel therapeutic strategies are discussed.

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Hull, Elizabeth. "Is Protein Misfolding and Aggregation a Common Disease Mechanism?" Journal of the Arizona-Nevada Academy of Science 39, no. 1 (January 2007): 14–17. http://dx.doi.org/10.2181/1533-6085(2007)39[14:ipmaaa]2.0.co;2.

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Soto, Claudio, and Sandra Pritzkow. "Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases." Nature Neuroscience 21, no. 10 (September 24, 2018): 1332–40. http://dx.doi.org/10.1038/s41593-018-0235-9.

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Gregersen, Niels, Lars Bolund, and Peter Bross. "Protein Misfolding, Aggregation, and Degradation in Disease." Molecular Biotechnology 31, no. 2 (2005): 141–50. http://dx.doi.org/10.1385/mb:31:2:141.

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Hoffmann, Armin, Krishna Neupane, and Michael T. Woodside. "Single-molecule assays for investigating protein misfolding and aggregation." Physical Chemistry Chemical Physics 15, no. 21 (2013): 7934. http://dx.doi.org/10.1039/c3cp44564j.

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Loureiro, Joana Angélica, Stéphanie Andrade, Lies Goderis, Ruben Gomez-Gutierrez, Claudio Soto, Rodrigo Morales, and Maria Carmo Pereira. "(De)stabilization of Alpha-Synuclein Fibrillary Aggregation by Charged and Uncharged Surfactants." International Journal of Molecular Sciences 22, no. 22 (November 19, 2021): 12509. http://dx.doi.org/10.3390/ijms222212509.

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder. An important hallmark of PD involves the pathological aggregation of proteins in structures known as Lewy bodies. The major component of these proteinaceous inclusions is alpha (α)-synuclein. In different conditions, α-synuclein can assume conformations rich in either α-helix or β-sheets. The mechanisms of α-synuclein misfolding, aggregation, and fibrillation remain unknown, but it is thought that β-sheet conformation of α-synuclein is responsible for its associated toxic mechanisms. To gain fundamental insights into the process of α-synuclein misfolding and aggregation, the secondary structure of this protein in the presence of charged and non-charged surfactant solutions was characterized. The selected surfactants were (anionic) sodium dodecyl sulphate (SDS), (cationic) cetyltrimethylammonium chloride (CTAC), and (uncharged) octyl β-D-glucopyranoside (OG). The effect of surfactants in α-synuclein misfolding was assessed by ultra-structural analyses, in vitro aggregation assays, and secondary structure analyses. The α-synuclein aggregation in the presence of negatively charged SDS suggests that SDS-monomer complexes stimulate the aggregation process. A reduction in the electrostatic repulsion between N- and C-terminal and in the hydrophobic interactions between the NAC (non-amyloid beta component) region and the C-terminal seems to be important to undergo aggregation. Fourier transform infrared spectroscopy (FTIR) measurements show that β-sheet structures comprise the assembly of the fibrils.

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Gerasimova, Elizaveta M., Sergey A. Fedotov, Daniel V. Kachkin, Elena S. Vashukova, Andrey S. Glotov, Yury O. Chernoff, and Aleksandr A. Rubel. "Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics." International Journal of Molecular Sciences 20, no. 24 (December 7, 2019): 6183. http://dx.doi.org/10.3390/ijms20246183.

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Preeclampsia (PE) is a multisystem heterogeneous complication of pregnancy remaining a leading cause of maternal and perinatal morbidity and mortality over the world. PE has a large spectrum of clinical features and symptoms, which make diagnosis challenging. Despite a long period of studying, PE etiology is still unclear and there are no reliable rapid tests for early diagnosis of this disease. During the last decade, it was shown that proteins misfolding and aggregation are associated with PE. Several proteins, including amyloid beta peptide, transthyretin, alpha-1 antitrypsin, albumin, IgG k-free light chains, and ceruloplasmin are dysregulated in PE, resulting in toxic deposition of amyloid-like aggregates in the placenta and body fluids. It is also possible that aggregated proteins induce defective trophoblast invasion, placental ischemia, ER stress, and promote PE manifestation. The fact that protein aggregation is an emerging biomarker of PE provides an opportunity to develop new diagnostic approaches based on amyloids special features, such as Congo red (CR) staining and thioflavin T (ThT) enhanced fluorescence.

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Malchiodi-Albedi, Fiorella, Silvia Paradisi, Andrea Matteucci, Claudio Frank, and Marco Diociaiuti. "Amyloid Oligomer Neurotoxicity, Calcium Dysregulation, and Lipid Rafts." International Journal of Alzheimer's Disease 2011 (2011): 1–17. http://dx.doi.org/10.4061/2011/906964.

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Amyloid proteins constitute a chemically heterogeneous group of proteins, which share some biophysical and biological characteristics, the principal of which are the high propensity to acquire an incorrect folding and the tendency to aggregate. A number of diseases are associated with misfolding and aggregation of proteins, although only in some of them—most notably Alzheimer's disease (AD) and transmissible spongiform encephalopathies (TSEs)—a pathogenetic link with misfolded proteins is now widely recognized. Lipid rafts (LRs) have been involved in the pathophysiology of diseases associated with protein misfolding at several levels, including aggregation of misfolded proteins, amyloidogenic processing, and neurotoxicity. Among the pathogenic misfolded proteins, the AD-related protein amyloid β (Aβ) is by far the most studied protein, and a large body of evidence has been gathered on the role played by LRs in Aβ pathogenicity. However, significant amount of data has also been collected for several other amyloid proteins, so that their ability to interact with LRs can be considered an additional, shared feature characterizing the amyloid protein family. In this paper, we will review the evidence on the role of LRs in the neurotoxicity of huntingtin, α-synuclein, prion protein, and calcitonin.

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Enam, Charisma, Yifat Geffen, Tommer Ravid, and Richard G. Gardner. "Protein Quality Control Degradation in the Nucleus." Annual Review of Biochemistry 87, no. 1 (June 20, 2018): 725–49. http://dx.doi.org/10.1146/annurev-biochem-062917-012730.

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Nuclear proteins participate in diverse cellular processes, many of which are essential for cell survival and viability. To maintain optimal nuclear physiology, the cell employs the ubiquitin-proteasome system to eliminate damaged and misfolded proteins in the nucleus that could otherwise harm the cell. In this review, we highlight the current knowledge about the major ubiquitin-protein ligases involved in protein quality control degradation (PQCD) in the nucleus and how they orchestrate their functions to eliminate misfolded proteins in different nuclear subcompartments. Many human disorders are causally linked to protein misfolding in the nucleus, hence we discuss major concepts that still need to be clarified to better understand the basis of the nuclear misfolded proteins’ toxic effects. Additionally, we touch upon potential strategies for manipulating nuclear PQCD pathways to ameliorate diseases associated with protein misfolding and aggregation in the nucleus.

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Sanz-Hernández, Máximo, and Alfonso De Simone. "Backbone NMR assignments of the C-terminal domain of the human prion protein and its disease‐associated T183A variant." Biomolecular NMR Assignments 15, no. 1 (February 15, 2021): 193–96. http://dx.doi.org/10.1007/s12104-021-10005-y.

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AbstractTransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the misfolding and aggregation of the human prion protein (huPrP). Despite efforts into investigating the process of huPrP aggregation, the mechanisms triggering its misfolding remain elusive. A number of TSE-associated mutations of huPrP have been identified, but their role at the onset and progression of prion diseases is unclear. Here we report the NMR assignments of the C-terminal globular domain of the wild type huPrP and the pathological mutant T183A. The differences in chemical shifts between the two variants reveal conformational alterations in some structural elements of the mutant, whereas the analyses of secondary shifts and random coil index provide indications on the putative mechanisms of misfolding of T183A huPrP.

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Journal articles on the topic 'Protein misfolding and aggregation'

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