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Journal articles on the topic 'Misfolding disease'

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Published: 9 March 2023

Last updated: 10 March 2023

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1

Bellotti, Vittorio, and Monica Stoppini. "Protein Misfolding Diseases." Open Biology Journal 2, no. 1 (December 31, 2009): 228–34. http://dx.doi.org/10.2174/1874196700902010228.

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Diseases caused by protein misfolding are an emerging pathologic category that are thought to share some basic common mechanisms and display impressive heterogeneity in terms of tissue involvement, age of onset and clinical features. The growing recognition of the impact that protein misfolding has on human diseases is certainly related to the phenomenon of population aging and the expansion of the population in which these diseases are more frequent, but it is also based on a scientific revolution that looks at protein dynamics and relates these data to their potential pathologic implications. The multidisciplinary exchange of knowledge between experts in apparently unrelated diseases, such as sickle cell anemia and Alzheimer’s disease, has helped clarify the pathogenesis of these and many other diseases. The quick expansion of knowledge on the mechanisms of these diseases is priming pharmaceutical research that is now providing the first prototype drugs.

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2

GUPTA, ARTI, and ANJALI PANDEY. "Protein misfolding and neurodegenerative disease." ASIAN SCIENCE 11, no. 1 (June 15, 2016): 69–73. http://dx.doi.org/10.15740/has/as/11.1/69-73.

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3

Dobson, Chris. "PROTEIN FOLDING, MISFOLDING AND DISEASE." Biochemical Society Transactions 28, no. 3 (June 1, 2000): A50. http://dx.doi.org/10.1042/bst028a050a.

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4

Hofmann, Christoph, Hugo A. Katus, and Shirin Doroudgar. "Protein Misfolding in Cardiac Disease." Circulation 139, no. 18 (April 30, 2019): 2085–88. http://dx.doi.org/10.1161/circulationaha.118.037417.

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5

Whiteman, Pat, Sarah Hutchinson, and Penny A. Handford. "Fibrillin-1 Misfolding and Disease." Antioxidants & Redox Signaling 8, no. 3-4 (March 2006): 338–46. http://dx.doi.org/10.1089/ars.2006.8.338.

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6

Dobson, Christopher M. "Protein misfolding, evolution and disease." Trends in Biochemical Sciences 24, no. 9 (September 1999): 329–32. http://dx.doi.org/10.1016/s0968-0004(99)01445-0.

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7

Moore, Roger A., Lara M. Taubner, and Suzette A. Priola. "Prion protein misfolding and disease." Current Opinion in Structural Biology 19, no. 1 (February 2009): 14–22. http://dx.doi.org/10.1016/j.sbi.2008.12.007.

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8

Ursini, Fulvio, Kelvin J. A. Davies, Matilde Maiorino, Tiziana Parasassi, and Alex Sevanian. "Atherosclerosis: another protein misfolding disease?" Trends in Molecular Medicine 8, no. 8 (August 2002): 370–74. http://dx.doi.org/10.1016/s1471-4914(02)02382-1.

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9

Hammarström, Per. "Protein folding, misfolding and disease." FEBS Letters 583, no. 16 (July 16, 2009): 2579–80. http://dx.doi.org/10.1016/j.febslet.2009.07.016.

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10

Gregersen, Niels, Peter Bross, Søren Vang, and Jane H. Christensen. "Protein Misfolding and Human Disease." Annual Review of Genomics and Human Genetics 7, no. 1 (September 2006): 103–24. http://dx.doi.org/10.1146/annurev.genom.7.080505.115737.

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11

Dobson, Christopher. "Protein Misfolding and Human Disease." Scientific World JOURNAL 2 (2002): 132. http://dx.doi.org/10.1100/tsw.2002.62.

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12

Smith, Anna, Bradley R. Groveman, Clayton Winkler, Katie Williams, Ryan Walters, Jue Yuan, Wenquan Zou, Karin Peterson, Simote T. Foliaki, and Cathryn L. Haigh. "Stress and viral insults do not trigger E200K PrP conversion in human cerebral organoids." PLOS ONE 17, no. 10 (October 27, 2022): e0277051. http://dx.doi.org/10.1371/journal.pone.0277051.

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Prion diseases are a group of rare, transmissible, and invariably fatal neurodegenerative diseases that affect both humans and animals. The cause of these diseases is misfolding of the prion protein into pathological isoforms called prions. Of all human prion diseases, 10–15% of cases are genetic and the E200K mutation, which causes familial Creutzfeldt-Jakob disease (CJD), is the most prevalent. For both sporadic and genetic disease, it remains uncertain as to how initial protein misfolding is triggered. Prior studies have linked protein misfolding with oxidative stress insults, deregulated interactions with cellular cofactors, and viral infections. Our previous work developed a cerebral organoid (CO) model using human induced pluripotent stem cells containing the E200K mutation. COs are three-dimensional human neural tissues that permit the study of host genetics and environmental factors that contribute to disease onset. Isogenically matched COs with and without the E200K mutation were used to investigate the propensity of E200K PrP to misfold following cellular insults associated with oxidative stress. Since viral infections have also been associated with oxidative stress and neurodegenerative diseases, we additionally investigated the influence of Herpes Simplex Type-1 virus (HSV1), a neurotropic virus that establishes life-long latent infection in its host, on E200K PrP misfolding. While COs proved to be highly infectable with HSV1, neither acute nor latent infection, or direct oxidative stress insult, resulted in evidence of E200K prion misfolding. We conclude that misfolding into seeding-active PrP species is not readily induced by oxidative stress or HSV1 in our organoid system.

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13

Chakraborty, Chiranjib, Shyam Nandi, and Snehasis Jana. "Prion Disease: A Deadly Disease for Protein Misfolding." Current Pharmaceutical Biotechnology 6, no. 2 (April 1, 2005): 167–77. http://dx.doi.org/10.2174/1389201053642321.

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14

Pande, Vijay. "Computational Nanomedicine: Simulating Protein Misfolding Disease." Biophysical Journal 98, no. 3 (January 2010): 223a. http://dx.doi.org/10.1016/j.bpj.2009.12.1207.

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15

Greene, C. M., and N. G. McElvaney. "Protein Misfolding and Obstructive Lung Disease." Proceedings of the American Thoracic Society 7, no. 6 (October 28, 2010): 346–55. http://dx.doi.org/10.1513/pats.201002-019aw.

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16

Breydo, Leonid, Jessica W. Wu, and Vladimir N. Uversky. "α-Synuclein misfolding and Parkinson's disease." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1822, no. 2 (February 2012): 261–85. http://dx.doi.org/10.1016/j.bbadis.2011.10.002.

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17

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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18

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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19

Wiseman, F., E. Cancellotti, and J. Manson. "Glycosylation and misfolding of PrP." Biochemical Society Transactions 33, no. 5 (October 26, 2005): 1094–95. http://dx.doi.org/10.1042/bst0331094.

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The TSEs (transmissible spongiform encephalopathies) are not only devastating neurological diseases but also provide a biochemical conundrum; how can a disease agent replicate in the apparent absence of genetic material? The prion hypothesis proposes that the TSE agent is a misfolded form of the host glycoprotein PrP (prion protein). However, a number of questions regarding the hypothesis remain to be addressed. We are using gene-targeted PrP transgenics models to investigate these issues. Here we discuss our recent results that examine the importance of PrP's N-glycans to the misfolding of the protein.

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20

Gandhi, Jason, Anthony C. Antonelli, Adil Afridi, Sohrab Vatsia, Gunjan Joshi, Victor Romanov, Ian V. J. Murray, and Sardar Ali Khan. "Protein misfolding and aggregation in neurodegenerative diseases: a review of pathogeneses, novel detection strategies, and potential therapeutics." Reviews in the Neurosciences 30, no. 4 (May 27, 2019): 339–58. http://dx.doi.org/10.1515/revneuro-2016-0035.

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Abstract Protein folding is a complex, multisystem process characterized by heavy molecular and cellular footprints. Chaperone machinery enables proper protein folding and stable conformation. Other pathways concomitant with the protein folding process include transcription, translation, post-translational modifications, degradation through the ubiquitin-proteasome system, and autophagy. As such, the folding process can go awry in several different ways. The pathogenic basis behind most neurodegenerative diseases is that the disruption of protein homeostasis (i.e. proteostasis) at any level will eventually lead to protein misfolding. Misfolded proteins often aggregate and accumulate to trigger neurotoxicity through cellular stress pathways and consequently cause neurodegenerative diseases. The manifestation of a disease is usually dependent on the specific brain region that the neurotoxicity affects. Neurodegenerative diseases are age-associated, and their incidence is expected to rise as humans continue to live longer and pursue a greater life expectancy. We presently review the sequelae of protein misfolding and aggregation, as well as the role of these phenomena in several neurodegenerative diseases including Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, transmissible spongiform encephalopathies, and spinocerebellar ataxia. Strategies for treatment and therapy are also conferred with respect to impairing, inhibiting, or reversing protein misfolding.

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21

Carlson, George A., and Stanley B. Prusiner. "How an Infection of Sheep Revealed Prion Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders." International Journal of Molecular Sciences 22, no. 9 (May 4, 2021): 4861. http://dx.doi.org/10.3390/ijms22094861.

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Although it is not yet universally accepted that all neurodegenerative diseases (NDs) are prion disorders, there is little disagreement that Alzheimer’s disease (AD), Parkinson’s disease, frontotemporal dementia (FTD), and other NDs are a consequence of protein misfolding, aggregation, and spread. This widely accepted perspective arose from the prion hypothesis, which resulted from investigations on scrapie, a common transmissible disease of sheep and goats. The prion hypothesis argued that the causative infectious agent of scrapie was a novel proteinaceous pathogen devoid of functional nucleic acids and distinct from viruses, viroids, and bacteria. At the time, it seemed impossible that an infectious agent like the one causing scrapie could replicate and exist as diverse microbiological strains without nucleic acids. However, aggregates of a misfolded host-encoded protein, designated the prion protein (PrP), were shown to be the cause of scrapie as well as Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker syndrome (GSS), which are similar NDs in humans. This review discusses historical research on diseases caused by PrP misfolding, emphasizing principles of pathogenesis that were later found to be core features of other NDs. For example, the discovery that familial prion diseases can be caused by mutations in PrP was important for understanding prion replication and disease susceptibility not only for rare PrP diseases but also for far more common NDs involving other proteins. We compare diseases caused by misfolding and aggregation of APP-derived Aβ peptides, tau, and α-synuclein with PrP prion disorders and argue for the classification of NDs caused by misfolding of these proteins as prion diseases. Deciphering the molecular pathogenesis of NDs as prion-mediated has provided new approaches for finding therapies for these intractable, invariably fatal disorders and has revolutionized the field.

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22

Jing, Jing, Gao Tu, Hongyan Yu, Rong Huang, Xianquan Ming, Haiqing Zhan, Feng Zhan, and Weiwei Xue. "Copper (Cu2+) ion-induced misfolding of tau protein R3 peptide revealed by enhanced molecular dynamics simulation." Physical Chemistry Chemical Physics 23, no. 20 (2021): 11717–26. http://dx.doi.org/10.1039/d0cp05744d.

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23

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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24

Fadiel, A., K. Eichenbaum, A. Hamza, O. Tuncalp, J. Luk, and F. Naftolin. "Protein Misfolding and Misprocessing in Complex Disease." Protein & Peptide Letters 12, no. 6 (August 1, 2005): 499–506. http://dx.doi.org/10.2174/0929866054395743.

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25

Howlett, David. "Protein Misfolding in Disease: Cause or Response?" Current Medicinal Chemistry-Immunology, Endocrine & Metabolic Agents 3, no. 4 (December 1, 2003): 371–83. http://dx.doi.org/10.2174/1568013033483285.

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26

Chiti, Fabrizio, and Christopher M. Dobson. "Protein Misfolding, Functional Amyloid, and Human Disease." Annual Review of Biochemistry 75, no. 1 (June 2006): 333–66. http://dx.doi.org/10.1146/annurev.biochem.75.101304.123901.

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27

Oláh, Judit, Ferenc Orosz, György M. Keserü, Zoltán Kovári, János Kovács, Susan Hollán, and Judit Ovádi. "Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease." Biochemical Society Transactions 30, no. 2 (April 1, 2002): 30–38. http://dx.doi.org/10.1042/bst0300030.

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A number of neurodegenerative diseases are mediated by mutation-induced protein misfolding. The resulting genetic defects, however, are expressed in varying phenotypes. Of the several well-established glycolytic enzyme deficiencies, triosephosphate isomerase (TPI) deficiency is the only one in which haemolytic anaemia is coupled with progressive, severe neurological disorder. In a Hungarian family with severe decrease in TPI activity, two germ line-identical but phenotypically differing compound heterozygote brothers inherited two independent (Phe240 → Leu and Glu145 → stop codon) mutations. We have demonstrated recently [Orosz, Oláh, Alvarez, Keserü, Szabó, Wágner, Kovári, Horányi, Baróti, Martial, Hollán and Ovádi (2001) Blood 98, 3106–3112] that the mutations of TPI explain in themselves neither the severe decrease in the enzyme activity characteristic of TPI deficiency nor the enhanced ability of the mutant enzyme from haemolysate of the propositus to associate with subcellular particles. Here we present kinetic (flux analysis), thermodynamic (microcalorimetry and fluorescence spectroscopy), structural (in silico) and ultrastructural (immunoelectron microscopy) data for characterization of mutant isomerase structures and for the TPI-related metabolic processes in normal and deficient cells. The relationships between mutation-induced TPI misfolding and formation of aberrant protein aggregates are discussed.

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28

Olah, Judit, Ferenc Orosz, Gyorgy Keseru, Janos Kovacs, Susan Hollan, and Judit Ovadi. "Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease." Biochemical Society Transactions 30, no. 1 (February 1, 2002): A6. http://dx.doi.org/10.1042/bst030a006a.

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29

Taubes, G. "Protein Chemistry: Misfolding the Way to Disease." Science 271, no. 5255 (March 15, 1996): 1493–95. http://dx.doi.org/10.1126/science.271.5255.1493.

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30

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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31

Horwich, Arthur L., and Jonathan S. Weissman. "Deadly Conformations—Protein Misfolding in Prion Disease." Cell 89, no. 4 (May 1997): 499–510. http://dx.doi.org/10.1016/s0092-8674(00)80232-9.

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32

Marrero-Winkens, Cristóbal, Charu Sankaran, and Hermann Schätzl. "From Seeds to Fibrils and Back: Fragmentation as an Overlooked Step in the Propagation of Prions and Prion-Like Proteins." Biomolecules 10, no. 9 (September 10, 2020): 1305. http://dx.doi.org/10.3390/biom10091305.

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Many devastating neurodegenerative diseases are driven by the misfolding of normal proteins into a pathogenic abnormal conformation. Examples of such protein misfolding diseases include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. The misfolded proteins involved in these diseases form self-templating oligomeric assemblies that recruit further correctly folded protein and induce their conversion. Over time, this leads to the formation of high molecular and mostly fibrillar aggregates that are increasingly inefficient at converting normal protein. Evidence from a multitude of in vitro models suggests that fibrils are fragmented to form new seeds, which can convert further normal protein and also spread to neighboring cells as observed in vivo. While fragmentation and seed generation were suggested as crucial steps in aggregate formation decades ago, the biological pathways involved remain largely unknown. Here, we show that mechanisms of aggregate clearance—namely the mammalian Hsp70–Hsp40–Hsp110 tri-chaperone system, macro-autophagy, and the proteasome system—may not only be protective, but also play a role in fragmentation. We further review the challenges that exist in determining the precise contribution of these mechanisms to protein misfolding diseases and suggest future directions to resolve these issues.

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33

Yadav, Kusum, Anurag Yadav, Priyanka Vashistha, Veda P. Pandey, and Upendra N. Dwivedi. "Protein Misfolding Diseases and Therapeutic Approaches." Current Protein & Peptide Science 20, no. 12 (December 16, 2019): 1226–45. http://dx.doi.org/10.2174/1389203720666190610092840.

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Protein folding is the process by which a polypeptide chain acquires its functional, native 3D structure. Protein misfolding, on the other hand, is a process in which protein fails to fold into its native functional conformation. This misfolding of proteins may lead to precipitation of a number of serious diseases such as Cystic Fibrosis (CF), Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Amyotrophic Lateral Sclerosis (ALS) etc. Protein Quality-control (PQC) systems, consisting of molecular chaperones, proteases and regulatory factors, help in protein folding and prevent its aggregation. At the same time, PQC systems also do sorting and removal of improperly folded polypeptides. Among the major types of PQC systems involved in protein homeostasis are cytosolic, Endoplasmic Reticulum (ER) and mitochondrial ones. The cytosol PQC system includes a large number of component chaperones, such as Nascent-polypeptide-associated Complex (NAC), Hsp40, Hsp70, prefoldin and T Complex Protein-1 (TCP-1) Ring Complex (TRiC). Protein misfolding diseases caused due to defective cytosolic PQC system include diseases involving keratin/collagen proteins, cardiomyopathies, phenylketonuria, PD and ALS. The components of PQC system of Endoplasmic Reticulum (ER) include Binding immunoglobulin Protein (BiP), Calnexin (CNX), Calreticulin (CRT), Glucose-regulated Protein GRP94, the thiol-disulphide oxidoreductases, Protein Disulphide Isomerase (PDI) and ERp57. ER-linked misfolding diseases include CF and Familial Neurohypophyseal Diabetes Insipidus (FNDI). The components of mitochondrial PQC system include mitochondrial chaperones such as the Hsp70, the Hsp60/Hsp10 and a set of proteases having AAA+ domains similar to the proteasome that are situated in the matrix or the inner membrane. Protein misfolding diseases caused due to defective mitochondrial PQC system include medium-chain acyl-CoA dehydrogenase (MCAD)/Short-chain Acyl-CoA Dehydrogenase (SCAD) deficiency diseases, hereditary spastic paraplegia. Among therapeutic approaches towards the treatment of various protein misfolding diseases, chaperones have been suggested as potential therapeutic molecules for target based treatment. Chaperones have been advantageous because of their efficient entry and distribution inside the cells, including specific cellular compartments, in therapeutic concentrations. Based on the chemical nature of the chaperones used for therapeutic purposes, molecular, chemical and pharmacological classes of chaperones have been discussed.

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Shimizu, Yu, Kiminori Nakamura, Aki Yoshii, Yuki Yokoi, Mani Kikuchi, Ryuga Shinozaki, Shunta Nakamura, Shuya Ohira, Rina Sugimoto, and Tokiyoshi Ayabe. "Paneth cell α-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice." Life Science Alliance 3, no. 6 (April 28, 2020): e201900592. http://dx.doi.org/10.26508/lsa.201900592.

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Crohn’s disease (CD) is an intractable inflammatory bowel disease, and dysbiosis, disruption of the intestinal microbiota, is associated with CD pathophysiology. ER stress, disruption of ER homeostasis in Paneth cells of the small intestine, and α-defensin misfolding have been reported in CD patients. Because α-defensins regulate the composition of the intestinal microbiota, their misfolding may cause dysbiosis. However, whether ER stress, α-defensin misfolding, and dysbiosis contribute to the pathophysiology of CD remains unknown. Here, we show that abnormal Paneth cells with markers of ER stress appear in SAMP1/YitFc, a mouse model of CD, along with disease progression. Those mice secrete reduced-form α-defensins that lack disulfide bonds into the intestinal lumen, a condition not found in normal mice, and reduced-form α-defensins correlate with dysbiosis during disease progression. Moreover, administration of reduced-form α-defensins to wild-type mice induces the dysbiosis. These data provide novel insights into CD pathogenesis induced by dysbiosis resulting from Paneth cell α-defensin misfolding and they suggest further that Paneth cells may be potential therapeutic targets.

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Bourgognon, Julie-Myrtille, Jereme G. Spiers, Sue W. Robinson, Hannah Scheiblich, Paul Glynn, Catharine Ortori, Sophie J. Bradley, Andrew B. Tobin, and Joern R. Steinert. "Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease." Proceedings of the National Academy of Sciences 118, no. 10 (March 2, 2021): e2009579118. http://dx.doi.org/10.1073/pnas.2009579118.

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Several neurodegenerative diseases associated with protein misfolding (Alzheimer’s and Parkinson’s disease) exhibit oxidative and nitrergic stress following initiation of neuroinflammatory pathways. Associated nitric oxide (NO)-mediated posttranslational modifications impact upon protein functions that can exacerbate pathology. Nonenzymatic and irreversible glycation signaling has been implicated as an underlying pathway that promotes protein misfolding, but the direct interactions between both pathways are poorly understood. Here we investigated the therapeutic potential of pharmacologically suppressing neuroinflammatory NO signaling during early disease progression of prion-infected mice. Mice were injected daily with an NO synthase (NOS) inhibitor at early disease stages, hippocampal gene and protein expression levels of oxidative and nitrergic stress markers were analyzed, and electrophysiological characterization of pyramidal CA1 neurons was performed. Increased neuroinflammatory signaling was observed in mice between 6 and 10 wk postinoculation (w.p.i.) with scrapie prion protein. Their hippocampi were characterized by enhanced nitrergic stress associated with a decline in neuronal function by 9 w.p.i. Daily in vivo administration of the NOS inhibitor L-NAME between 6 and 9 w.p.i. at 20 mg/kg prevented the functional degeneration of hippocampal neurons in prion-diseased mice. We further found that this intervention in diseased mice reduced 3-nitrotyrosination of triose-phosphate isomerase, an enzyme involved in the formation of disease-associated glycation. Furthermore, L-NAME application led to a reduced expression of the receptor for advanced glycation end-products and the diminished accumulation of hippocampal prion misfolding. Our data suggest that suppressing neuroinflammatory NO signaling slows functional neurodegeneration and reduces nitrergic and glycation-associated cellular stress.

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36

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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37

Barden, C., F. Meier-Stephenson, MD Carter, S. Banfield, EC Diez, B. Kelly, E. Lu, et al. "Design and development of drugs for Alzheimer’s dementia as a protein misfolding disorder." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 42, S1 (May 2015): S16. http://dx.doi.org/10.1017/cjn.2015.95.

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Background: There are no disease modifying agents for the treatment of Alzheimer’s disease (AD). Pathologically, AD is associated with the misfolding of two peptides: beta-amyloid (plaques) and tau (tangles). Methods: Using large-scale computer simulations, we modelled the misfolding of both beta-amyloid and tau, identifying a common conformational motif (CCM; i.e. an abnormal peptide shape), present in both beta-amyloid and tau, that promotes their misfolding. We screened a library of 11.8 million compounds against this in silico model of protein misfolding, identifying three novel molecular classes of putative therapeutics as anti-protein misfolding agents. We synthesized approximately 400 new chemical entity drug-like molecules in each of these three classes (i.e. 1200 potential drug candidates). These were comprehensively screened in a battery of five in vitro protein oligomerization assays. Selected compounds were next evaluated in the APP/PS1 doubly transgenic mouse model of AD. Results: Two new classes of molecules were identified with the ability to block the oligomerization of both beta-amyloid and tau. These compounds are drug-like with good pharmacokinetic properties and are brain-penetrant. They exhibit excellent efficacy in transgenic mouse models. Conclusion: Computer aided drug design has enabled the discovery of novel drug-like molecules able to inhibit both tau and beta-amyloid misfolding.

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Norton, Heidi K., and Jennifer E. Phillips-Cremins. "Crossed wires: 3D genome misfolding in human disease." Journal of Cell Biology 216, no. 11 (August 30, 2017): 3441–52. http://dx.doi.org/10.1083/jcb.201611001.

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Mammalian genomes are folded into unique topological structures that undergo precise spatiotemporal restructuring during healthy development. Here, we highlight recent advances in our understanding of how the genome folds inside the 3D nucleus and how these folding patterns are miswired during the onset and progression of mammalian disease states. We discuss potential mechanisms underlying the link among genome misfolding, genome dysregulation, and aberrant cellular phenotypes. We also discuss cases in which the endogenous 3D genome configurations in healthy cells might be particularly susceptible to mutation or translocation. Together, these data support an emerging model in which genome folding and misfolding is critically linked to the onset and progression of a broad range of human diseases.

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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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Broom, Helen R., Jessica A. O. Rumfeldt, and Elizabeth M. Meiering. "Many roads lead to Rome? Multiple modes of Cu,Zn superoxide dismutase destabilization, misfolding and aggregation in amyotrophic lateral sclerosis." Essays in Biochemistry 56 (August 18, 2014): 149–65. http://dx.doi.org/10.1042/bse0560149.

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ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative syndrome characterized by progressive paralysis and motor neuron death. Although the pathological mechanisms that cause ALS remain unclear, accumulating evidence supports that ALS is a protein misfolding disorder. Mutations in Cu,Zn-SOD1 (copper/zinc superoxide dismutase 1) are a common cause of familial ALS. They have complex effects on different forms of SOD1, but generally destabilize the protein and enhance various modes of misfolding and aggregation. In addition, there is some evidence that destabilized covalently modified wild-type SOD1 may be involved in disease. Among the multitude of misfolded/aggregated species observed for SOD1, multiple species may impair various cellular components at different disease stages. Newly developed antibodies that recognize different structural features of SOD1 represent a powerful tool for further unravelling the roles of different SOD1 structures in disease. Evidence for similar cellular targets of misfolded/aggregated proteins, loss of cellular proteostasis and cell–cell transmission of aggregates point to common pathological mechanisms between ALS and other misfolding diseases, such as Alzheimer's, Parkinson's and prion diseases, as well as serpinopathies. The recent progress in understanding the molecular basis for these devastating diseases provides numerous avenues for developing urgently needed therapeutics.

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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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Fändrich, Marcus, and Matthias Schmidt. "Methods to study the structure of misfolded protein states in systemic amyloidosis." Biochemical Society Transactions 49, no. 2 (April 30, 2021): 977–85. http://dx.doi.org/10.1042/bst20201022.

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Systemic amyloidosis is defined as a protein misfolding disease in which the amyloid is not necessarily deposited within the same organ that produces the fibril precursor protein. There are different types of systemic amyloidosis, depending on the protein constructing the fibrils. This review will focus on recent advances made in the understanding of the structural basis of three major forms of systemic amyloidosis: systemic AA, AL and ATTR amyloidosis. The three diseases arise from the misfolding of serum amyloid A protein, immunoglobulin light chains or transthyretin. The presented advances in understanding were enabled by recent progress in the methodology available to study amyloid structures and protein misfolding, in particular concerning cryo-electron microscopy (cryo-EM) and nuclear magnetic resonance (NMR) spectroscopy. An important observation made with these techniques is that the structures of previously described in vitro formed amyloid fibrils did not correlate with the structures of amyloid fibrils extracted from diseased tissue, and that in vitro fibrils were typically more protease sensitive. It is thus possible that ex vivo fibrils were selected in vivo by their proteolytic stability.

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Tsao, Francis H. C., and Keith C. Meyer. "Human Serum Albumin Misfolding in Aging and Disease." International Journal of Molecular Sciences 23, no. 19 (October 2, 2022): 11675. http://dx.doi.org/10.3390/ijms231911675.

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Age-dependent conformational stability of human serum albumin was determined by the method of fluorescent bilayer liposome assay. After pre-heating at 80 °C, albumin in the sera of 74-year-old healthy subjects exhibited hydrophobic effects on liposomes and made liposomal membrane phospholipids more susceptible to hydrolysis by the lipolytic enzyme phospholipase A2. In contrast, albumin in the sera of 24-year-old individuals was stable at 80 °C and displayed no increased hydrophobic effects on liposomes. The results suggest that albumin in the sera of 74-year-old subjects is more easily converted to a misfolded form in which its protein structure is altered when compared to albumin in the sera of 24-year-old individuals. Misfolded albumin can lose its ability to carry out its normal homeostatic functions and may promote alterations in membrane integrity under inflammatory conditions. However, our investigation has limitations that include the lack of testing sera from large numbers of individuals across a broad range of age to validate our preliminary observations of age-dependent differences in albumin stability and its interactions with liposomes.

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M. Gomes, Claudio. "Protein Misfolding in Disease and Small Molecule Therapies." Current Topics in Medicinal Chemistry 12, no. 22 (March 1, 2013): 2460–69. http://dx.doi.org/10.2174/1568026611212220002.

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Gomes, Claudio M. "Protein Misfolding in Disease and Small Molecule Therapies." Current Topics in Medicinal Chemistry 999, no. 999 (February 1, 2013): 36–42. http://dx.doi.org/10.2174/15680266112129990069.

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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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Dobson, C. M. "Protein misfolding and its links with human disease." Biochemical Society Transactions 30, no. 3 (June 1, 2002): A53. http://dx.doi.org/10.1042/bst030a053c.

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Zhang, Q., E. T. Powers, J. Nieva, M. E. Huff, M. A. Dendle, J. Bieschke, C. G. Glabe, et al. "Metabolite-initiated protein misfolding may trigger Alzheimer's disease." Proceedings of the National Academy of Sciences 101, no. 14 (March 19, 2004): 4752–57. http://dx.doi.org/10.1073/pnas.0400924101.

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Mukherjee, Abhisek, Diego Morales-Scheihing, Peter C. Butler, and Claudio Soto. "Type 2 diabetes as a protein misfolding disease." Trends in Molecular Medicine 21, no. 7 (July 2015): 439–49. http://dx.doi.org/10.1016/j.molmed.2015.04.005.

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Soto, Claudio. "Protein misfolding and disease; protein refolding and therapy." FEBS Letters 498, no. 2-3 (June 8, 2001): 204–7. http://dx.doi.org/10.1016/s0014-5793(01)02486-3.

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