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1
Limanaqi, Fiona, Francesca Biagioni, Carla Letizia Busceti, Larisa Ryskalin, Maico Polzella, Alessandro Frati, and Francesco Fornai. "Phytochemicals Bridging Autophagy Induction and Alpha-Synuclein Degradation in Parkinsonism." International Journal of Molecular Sciences 20, no. 13 (July 3, 2019): 3274. http://dx.doi.org/10.3390/ijms20133274.
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Among nutraceuticals, phytochemical-rich compounds represent a source of naturally-derived bioactive principles, which are extensively studied for potential beneficial effects in a variety of disorders ranging from cardiovascular and metabolic diseases to cancer and neurodegeneration. In the brain, phytochemicals produce a number of biological effects such as modulation of neurotransmitter activity, growth factor induction, antioxidant and anti-inflammatory activity, stem cell modulation/neurogenesis, regulation of mitochondrial homeostasis, and counteracting protein aggregation through modulation of protein-folding chaperones and the cell clearing systems autophagy and proteasome. In particular, the ability of phytochemicals in restoring proteostasis through autophagy induction took center stage in recent research on neurodegenerative disorders such as Parkinson’s disease (PD). Indeed, autophagy dysfunctions and α-syn aggregation represent two interdependent downstream biochemical events, which concur in the parkinsonian brain, and which are targeted by phytochemicals administration. Therefore, in the present review we discuss evidence about the autophagy-based neuroprotective effects of specific phytochemical-rich plants in experimental parkinsonism, with a special focus on their ability to counteract alpha-synuclein aggregation and toxicity. Although further studies are needed to confirm the autophagy-based effects of some phytochemicals in parkinsonism, the evidence discussed here suggests that rescuing autophagy through natural compounds may play a role in preserving dopamine (DA) neuron integrity by counteracting the aggregation, toxicity, and prion-like spreading of α-syn, which remains a hallmark of PD.
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de Boni, Laura, Aurelia Hays Watson, Ludovica Zaccagnini, Amber Wallis, Kristina Zhelcheska, Nora Kim, John Sanderson, et al. "Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by α-synuclein conformations." Acta Neuropathologica 143, no. 4 (February 9, 2022): 453–69. http://dx.doi.org/10.1007/s00401-022-02406-7.
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AbstractThe protein α-synuclein, a key player in Parkinson’s disease (PD) and other synucleinopathies, exists in different physiological conformations: cytosolic unfolded aggregation-prone monomers and helical aggregation-resistant multimers. It has been shown that familial PD-associated missense mutations within the α-synuclein gene destabilize the conformer equilibrium of physiologic α-synuclein in favor of unfolded monomers. Here, we characterized the relative levels of unfolded and helical forms of cytosolic α-synuclein in post-mortem human brain tissue and showed that the equilibrium of α-synuclein conformations is destabilized in sporadic PD and DLB patients. This disturbed equilibrium is decreased in a brain region-specific manner in patient samples pointing toward a possible “prion-like” propagation of the underlying pathology and forms distinct disease-specific patterns in the two different synucleinopathies. We are also able to show that a destabilization of multimers mechanistically leads to increased levels of insoluble, pathological α-synuclein, while pharmacological stabilization of multimers leads to a “prion-like” aggregation resistance. Together, our findings suggest that these disease-specific patterns of α-synuclein multimer destabilization in sporadic PD and DLB are caused by both regional neuronal vulnerability and “prion-like” aggregation transmission enabled by the destabilization of local endogenous α-synuclein protein.
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Chen, Merry, Julie Vincent, Alexis Ezeanii, Saurabh Wakade, Shobha Yerigenahally, and Danielle E. Mor. "Heparan sulfate proteoglycans mediate prion-like α-synuclein toxicity in Parkinson’s in vivo models." Life Science Alliance 5, no. 11 (July 5, 2022): e202201366. http://dx.doi.org/10.26508/lsa.202201366.
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Parkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of α-synuclein protein. Growing evidence suggests that α-synuclein aggregates may spread from neurons of the digestive tract to the central nervous system in a prion-like manner, yet the mechanisms of α-synuclein transmission and neurotoxicity remain poorly understood. Animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first Caenorhabditis elegans models in which feeding with α-synuclein preformed fibrils (PFFs) induces dopaminergic neurodegeneration, prion-like seeding of aggregation of human α-synuclein expressed in the host, and an associated motor decline. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, or other enzymes involved in heparan sulfate proteoglycan synthesis, protected against PFF-induced α-synuclein aggregation, motor dysfunction, and dopamine neuron degeneration. This work offers new models by which to investigate gut-derived α-synuclein spreading and propagation of disease.
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Iljina, Marija, Gonzalo A. Garcia, Mathew H. Horrocks, Laura Tosatto, Minee L. Choi, Kristina A. Ganzinger, Andrey Y. Abramov, et al. "Kinetic model of the aggregation of alpha-synuclein provides insights into prion-like spreading." Proceedings of the National Academy of Sciences 113, no. 9 (February 16, 2016): E1206—E1215. http://dx.doi.org/10.1073/pnas.1524128113.
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The protein alpha-synuclein (αS) self-assembles into small oligomeric species and subsequently into amyloid fibrils that accumulate and proliferate during the development of Parkinson’s disease. However, the quantitative characterization of the aggregation and spreading of αS remains challenging to achieve. Previously, we identified a conformational conversion step leading from the initially formed oligomers to more compact oligomers preceding fibril formation. Here, by a combination of single-molecule fluorescence measurements and kinetic analysis, we find that the reaction in solution involves two unimolecular structural conversion steps, from the disordered to more compact oligomers and then to fibrils, which can elongate by further monomer addition. We have obtained individual rate constants for these key microscopic steps by applying a global kinetic analysis to both the decrease in the concentration of monomeric protein molecules and the increase in oligomer concentrations over a 0.5–140-µM range of αS. The resulting explicit kinetic model of αS aggregation has been used to quantitatively explore seeding the reaction by either the compact oligomers or fibrils. Our predictions reveal that, although fibrils are more effective at seeding than oligomers, very high numbers of seeds of either type, of the order of 104, are required to achieve efficient seeding and bypass the slow generation of aggregates through primary nucleation. Complementary cellular experiments demonstrated that two orders of magnitude lower numbers of oligomers were sufficient to generate high levels of reactive oxygen species, suggesting that effective templated seeding is likely to require both the presence of template aggregates and conditions of cellular stress.
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Medvedeva, Maria, Natalia Kitsilovskaya, Yulia Stroylova, Irina Sevostyanova, Ali Akbar Saboury, and Vladimir Muronetz. "Hydroxycinnamic Acid Derivatives from Coffee Extracts Prevent Amyloid Transformation of Alpha-Synuclein." Biomedicines 10, no. 9 (September 12, 2022): 2255. http://dx.doi.org/10.3390/biomedicines10092255.
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Earlier we showed that derivatives of hydroxycinnamic acids prevent amyloid transformation of alpha-synuclein and prion protein. The aim of this work was to determine the content of 3-hydroxycinnamic acid derivatives in coffee extracts and to evaluate their activity in relation to alpha-synuclein amyloid aggregation. Hydroxycinnamic acid derivatives were identified in aqueous and ethanol extracts of coffee beans by quantitative mass spectrometric analysis. Only 3,4-dimethoxycinnamic acid (13–53 μg/mL) was detected in significant amounts in the coffee extracts, while ferulic acid was present in trace amounts. In addition, 3-methoxy-4-acetamidoxycinnamic acid (0.4–0.8 μg/mL) was detected in the roasted coffee extracts. The half-maximum inhibitory concentrations of alpha-synuclein fibrillization reaction in the presence of coffee extracts, as well as inhibitory constants, were determined using thioflavin T assay. The inhibitory effect of black and green coffee extracts on alpha-synuclein fibrillization is dose-dependent, and in a pairwise comparison, the constants of half-maximal inhibition of fibrillization for green coffee extracts are comparable to or greater than those for black coffee. Thus, coffee extracts prevent pathological transformation of alpha-synuclein in vitro, probably due to the presence of 3,4-dimethoxycinnamic acid in them. Consequently, coffee drinks and coffee extracts can be used for the prevention of synucleinopathies including Parkinson’s disease.
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Prusiner, Stanley B., Amanda L. Woerman, Daniel A. Mordes, Joel C. Watts, Ryan Rampersaud, David B. Berry, Smita Patel, et al. "Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism." Proceedings of the National Academy of Sciences 112, no. 38 (August 31, 2015): E5308—E5317. http://dx.doi.org/10.1073/pnas.1514475112.
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Prions are proteins that adopt alternative conformations that become self-propagating; the PrPSc prion causes the rare human disorder Creutzfeldt–Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T–YFP) and TgM83+/− mice expressing α-synuclein (A53T). The TgM83+/− mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83+/+ mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83+/− mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T–YFP in cultured cells, whereas none of six Parkinson’s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83+/+ mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.
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Piccardo, Pedro, Juraj Cervenak, Ming Bu, Lindsay Miller, and David M. Asher. "Complex proteinopathy with accumulations of prion protein, hyperphosphorylated tau, α-synuclein and ubiquitin in experimental bovine spongiform encephalopathy of monkeys." Journal of General Virology 95, no. 7 (July 1, 2014): 1612–18. http://dx.doi.org/10.1099/vir.0.062083-0.
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Proteins aggregate in several slowly progressive neurodegenerative diseases called ‘proteinopathies’. Studies with cell cultures and transgenic mice overexpressing mutated proteins suggested that aggregates of one protein induced misfolding and aggregation of other proteins as well – a possible common mechanism for some neurodegenerative diseases. However, most proteinopathies are ‘sporadic’, without gene mutation or overexpression. Thus, proteinopathies in WT animals genetically close to humans might be informative. Squirrel monkeys infected with the classical bovine spongiform encephalopathy agent developed an encephalopathy resembling variant Creutzfeldt–Jakob disease with accumulations not only of abnormal prion protein (PrPTSE), but also three other proteins: hyperphosphorylated tau (p-tau), α-synuclein and ubiquitin; β-amyloid protein (Aβ) did not accumulate. Severity of brain lesions correlated with spongiform degeneration. No amyloid was detected. These results suggested that PrPTSE enhanced formation of p-tau and aggregation of α-synuclein and ubiquitin, but not Aβ, providing a new experimental model for neurodegenerative diseases associated with complex proteinopathies.
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Vaquer-Alicea, Jaime, and Marc I. Diamond. "Propagation of Protein Aggregation in Neurodegenerative Diseases." Annual Review of Biochemistry 88, no. 1 (June 20, 2019): 785–810. http://dx.doi.org/10.1146/annurev-biochem-061516-045049.
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Most common neurodegenerative diseases feature deposition of protein amyloids and degeneration of brain networks. Amyloids are ordered protein assemblies that can act as templates for their own replication through monomer addition. Evidence suggests that this characteristic may underlie the progression of pathology in neurodegenerative diseases. Many different amyloid proteins, including Aβ, tau, and α-synuclein, exhibit properties similar to those of infectious prion protein in experimental systems: discrete and self-replicating amyloid structures, transcellular propagation of aggregation, and transmissible neuropathology. This review discusses the contribution of prion phenomena and transcellular propagation to the progression of pathology in common neurodegenerative diseases such as Alzheimer's and Parkinson's. It reviews fundamental events such as cell entry, amplification, and transcellular movement. It also discusses amyloid strains, which produce distinct patterns of neuropathology and spread through the nervous system. These concepts may impact the development of new diagnostic and therapeutic strategies.
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Jan, Asad, Nádia Pereira Gonçalves, Christian Bjerggaard Vaegter, Poul Henning Jensen, and Nelson Ferreira. "The Prion-Like Spreading of Alpha-Synuclein in Parkinson’s Disease: Update on Models and Hypotheses." International Journal of Molecular Sciences 22, no. 15 (August 3, 2021): 8338. http://dx.doi.org/10.3390/ijms22158338.
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The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson’s disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of α-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies.
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Crestini, Alessio, Francesca Santilli, Stefano Martellucci, Elena Carbone, Maurizio Sorice, Paola Piscopo, and Vincenzo Mattei. "Prions and Neurodegenerative Diseases: A Focus on Alzheimer’s Disease." Journal of Alzheimer's Disease 85, no. 2 (January 18, 2022): 503–18. http://dx.doi.org/10.3233/jad-215171.
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Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer’s disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.
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Longhena, Francesca, Gaia Faustini, Cristina Missale, Marina Pizzi, PierFranco Spano, and Arianna Bellucci. "The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy." Neural Plasticity 2017 (2017): 1–15. http://dx.doi.org/10.1155/2017/5012129.
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Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson’s disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related toα-synuclein deposition at synaptic sites. Indeed,α-synuclein accumulation can impair synaptic dopamine release and induces the death of nigrostriatal neurons. While in physiological conditions the protein can interact with and modulate synaptic vesicle proteins and membranes, numerous experimental evidences have confirmed that its pathological aggregation can compromise correct neuronal functioning. In addition, recent findings indicate thatα-synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillaryα-synuclein can move from cell to cell and can trigger the aggregation of the endogenous protein in recipient neurons. This novel “prion-like” behavior could further contribute to synaptic failure in PD and other synucleinopathies. This review describes the major findings supporting the occurrence ofα-synuclein pathology propagation in PD and discusses how this phenomenon could induce or contribute to synaptic injury and degeneration.
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Austen, Brian M., Joseph M. Sheridan, Omar M. A. El-Agnaf, Hazel Goodwin, and Emma R. Frears. "Improved solid-phase syntheses of amyloid proteins associated with neurodegenerative diseases." Protein & Peptide Letters 7, no. 1 (February 2000): 1–8. http://dx.doi.org/10.2174/092986650701221205144944.
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P-Amyloid protein, the a-synuclein fragment NAC, and protease-resistant forms of prion proteins are found deposited in the pathological lesions associated with neurodegenerative disease. Chemical syntheses of these proteins are notoriously difficult due to aggregation of the peptides on the resin during synthesis. We report optimised solid-phase syntheses of several amyloid peptides in high yield and >90% initial purity.
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Singh, Serena, and Mari L. DeMarco. "In Vitro Conversion Assays Diagnostic for Neurodegenerative Proteinopathies." Journal of Applied Laboratory Medicine 5, no. 1 (December 30, 2019): 142–57. http://dx.doi.org/10.1373/jalm.2019.029801.
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Abstract Background In vitro conversion assays, including real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) techniques, were first developed to study the conversion process of the prion protein to its misfolded, disease-associated conformation. The intrinsic property of prion proteins to propagate their misfolded structure was later exploited to detect subfemtogram quantities of the misfolded protein present in tissues and fluids from humans and animals with transmissible spongiform encephalopathies. Currently, conversion assays are used clinically as sensitive and specific diagnostic tools for antemortem diagnosis of prion disease. Content In vitro conversion assays are now being applied to the development of diagnostics for related neurodegenerative diseases, including detection of misfolded α-synuclein in Parkinson disease, misfolded amyloid-β in Alzheimer disease, and misfolded tau in Pick disease. Like the predicate prion protein in vitro conversion diagnostics, these assays exploit the ability of endogenously misfolded proteins to induce misfolding and aggregation of their natively folded counterpart in vitro. This property enables biomarker detection of the underlying protein pathology. Herein, we review RT-QuIC and PMCA for (a) prion-, (b) α-synuclein-, (c) amyloid-β-, and (d) tau-opathies. Summary Although already in routine clinical use for the detection of transmissible spongiform encephalopathies, in vitro conversion assays for other neurodegenerative disorders require further development and evaluation of diagnostic performance before consideration for clinical implementation.
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Marreiros, Rita, Andreas Müller-Schiffmann, Svenja V. Trossbach, Ingrid Prikulis, Sebastian Hänsch, Stefanie Weidtkamp-Peters, Ana Raquel Moreira, et al. "Disruption of cellular proteostasis by H1N1 influenza A virus causes α-synuclein aggregation." Proceedings of the National Academy of Sciences 117, no. 12 (March 9, 2020): 6741–51. http://dx.doi.org/10.1073/pnas.1906466117.
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Neurodegenerative diseases feature specific misfolded or misassembled proteins associated with neurotoxicity. The precise mechanisms by which protein aggregates first arise in the majority of sporadic cases have remained unclear. Likely, a first critical mass of misfolded proteins starts a vicious cycle of a prion-like expansion. We hypothesize that viruses, having evolved to hijack the host cellular machinery for catalyzing their replication, lead to profound disturbances of cellular proteostasis, resulting in such a critical mass of protein aggregates. Here, we investigated the effect of influenza virus (H1N1) strains on proteostasis of proteins associated with neurodegenerative diseases in Lund human mesencephalic dopaminergic cells in vitro and infection ofRagknockout mice in vivo. We demonstrate that acute H1N1 infection leads to the formation of α-synuclein and Disrupted-in-Schizophrenia 1 (DISC1) aggregates, but not of tau or TDP-43 aggregates, indicating a selective effect on proteostasis. Oseltamivir phosphate, an antiinfluenza drug, prevented H1N1-induced α-synuclein aggregation. As a cell pathobiological mechanism, we identified H1N1-induced blocking of autophagosome formation and inhibition of autophagic flux. In addition, α-synuclein aggregates appeared in infected cell populations connected to the olfactory bulbs following intranasal instillation of H1N1 inRagknockout mice. We propose that H1N1 virus replication in neuronal cells can induce seeds of aggregated α-synuclein or DISC1 that may be able to initiate further detrimental downstream events and should thus be considered a risk factor in the pathogenesis of synucleinopathies or a subset of mental disorders. More generally, aberrant proteostasis induced by viruses may be an underappreciated factor in initiating protein misfolding.
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Tabner, B. J., S. Turnbull, N. J. Fullwood, M. German, and D. Allsop. "The production of hydrogen peroxide during early-stage protein aggregation: a common pathological mechanism in different neurodegenerative diseases?" Biochemical Society Transactions 33, no. 4 (August 1, 2005): 548–50. http://dx.doi.org/10.1042/bst0330548.
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By means of an ESR spin-trapping method, we have shown that Aβ (amyloid β), α-synuclein and various toxic forms of the prion protein all appear to generate H2O2in vitro. A fundamental molecular mechanism underlying the pathogenesis of cell death in several different neurodegenerative diseases could be the direct production of H2O2 during the early stages of protein aggregation.
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Xia, Yuxing, Grace M. Lloyd, and Benoit I. Giasson. "Targeted proteolytic products of τ and α-synuclein in neurodegeneration." Essays in Biochemistry 65, no. 7 (December 2021): 905–12. http://dx.doi.org/10.1042/ebc20210028.
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Abstract CNS pathological inclusions comprising τ or α-synuclein (αSyn) define a spectrum of neurodegenerative diseases, and these can often present concurrently in the same individuals. The aggregation of both proteins is clearly associated with neurodegeneration and the deleterious properties of each protein is further supported by mutations in each gene (MAPT and SNCA, respectively) resulting in disease. The initiating events in most sporadic neurodegenerative diseases are still unclear but growing evidence suggests that the aberrant proteolytic cleavage of τ and αSyn results in products that can be toxic and/or initiate aggregation that can further spread by a prion-like mechanism. The accumulation of some of these cleavage products can further potentiate the progression of protein aggregation transmission and lead to their accumulation in peripheral biofluids such as cerebrospinal fluid (CSF) and blood. The future development of new tools to detect specific τ and αSyn abnormal cleavage products in peripheral biofluids could be useful biomarkers and better understand of the role of unique proteolytic activities could yield therapeutic interventions.
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Costanzo, Maddalena, and Chiara Zurzolo. "The cell biology of prion-like spread of protein aggregates: mechanisms and implication in neurodegeneration." Biochemical Journal 452, no. 1 (April 25, 2013): 1–17. http://dx.doi.org/10.1042/bj20121898.
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The misfolding and aggregation of specific proteins is a common hallmark of many neurodegenerative disorders, including highly prevalent illnesses such as Alzheimer's and Parkinson's diseases, as well as rarer disorders such as Huntington's and prion diseases. Among these, only prion diseases are ‘infectious’. By seeding misfolding of the PrPC (normal conformer prion protein) into PrPSc (abnormal disease-specific conformation of prion protein), prions spread from the periphery of the body to the central nervous system and can also be transmitted between individuals of the same or different species. However, recent exciting data suggest that the transmissibility of misfolded proteins within the brain is a property that goes way beyond the rare prion diseases. Evidence indicates that non-prion aggregates [tau, α-syn (α-synuclein), Aβ (amyloid-β) and Htt (huntingtin) aggregates] can also move between cells and seed the misfolding of their normal conformers. These findings have enormous implications. On the one hand they question the therapeutical use of transplants, and on the other they indicate that it may be possible to bring these diseases to an early arrest by preventing cell-to-cell transmission. To better understand the prion-like spread of these protein aggregates it is essential to identify the underlying cellular and molecular factors. In the present review we analyse and discuss the evidence supporting prion-like spreading of amyloidogenic proteins, especially focusing on the cellular and molecular mechanisms and their significance.
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Villar-Piqué, Anna, Tomás Lopes da Fonseca, Ricardo Sant’Anna, Éva Mónika Szegö, Luis Fonseca-Ornelas, Raquel Pinho, Anita Carija, et al. "Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity." Proceedings of the National Academy of Sciences 113, no. 42 (October 5, 2016): E6506—E6515. http://dx.doi.org/10.1073/pnas.1606791113.
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Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.
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Pinotsi, Dorothea, Claire H. Michel, Alexander K. Buell, Romain F. Laine, Pierre Mahou, Christopher M. Dobson, Clemens F. Kaminski, and Gabriele S. Kaminski Schierle. "Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in neurons." Proceedings of the National Academy of Sciences 113, no. 14 (March 18, 2016): 3815–19. http://dx.doi.org/10.1073/pnas.1516546113.
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New strategies for visualizing self-assembly processes at the nanoscale give deep insights into the molecular origins of disease. An example is the self-assembly of misfolded proteins into amyloid fibrils, which is related to a range of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. Here, we probe the links between the mechanism of α-synuclein (AS) aggregation and its associated toxicity by using optical nanoscopy directly in a neuronal cell culture model of Parkinson’s disease. Using superresolution microscopy, we show that protein fibrils are taken up by neuronal cells and act as prion-like seeds for elongation reactions that both consume endogenous AS and suppress its de novo aggregation. When AS is internalized in its monomeric form, however, it nucleates and triggers the aggregation of endogenous AS, leading to apoptosis, although there are no detectable cross-reactions between externally added and endogenous protein species. Monomer-induced apoptosis can be reduced by pretreatment with seed fibrils, suggesting that partial consumption of the externally added or excess soluble AS can be significantly neuroprotective.
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Sorrentino, Zachary A., and Benoit I. Giasson. "The emerging role of α-synuclein truncation in aggregation and disease." Journal of Biological Chemistry 295, no. 30 (May 18, 2020): 10224–44. http://dx.doi.org/10.1074/jbc.rev120.011743.
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α-Synuclein (αsyn) is an abundant brain neuronal protein that can misfold and polymerize to form toxic fibrils coalescing into pathologic inclusions in neurodegenerative diseases, including Parkinson's disease, Lewy body dementia, and multiple system atrophy. These fibrils may induce further αsyn misfolding and propagation of pathologic fibrils in a prion-like process. It is unclear why αsyn initially misfolds, but a growing body of literature suggests a critical role of partial proteolytic processing resulting in various truncations of the highly charged and flexible carboxyl-terminal region. This review aims to 1) summarize recent evidence that disease-specific proteolytic truncations of αsyn occur in Parkinson's disease, Lewy body dementia, and multiple system atrophy and animal disease models; 2) provide mechanistic insights on how truncation of the amino and carboxyl regions of αsyn may modulate the propensity of αsyn to pathologically misfold; 3) compare experiments evaluating the prion-like properties of truncated forms of αsyn in various models with implications for disease progression; 4) assess uniquely toxic properties imparted to αsyn upon truncation; and 5) discuss pathways through which truncated αsyn forms and therapies targeted to interrupt them. Cumulatively, it is evident that truncation of αsyn, particularly carboxyl truncation that can be augmented by dysfunctional proteostasis, dramatically potentiates the propensity of αsyn to pathologically misfold into uniquely toxic fibrils with modulated prion-like seeding activity. Therapeutic strategies and experimental paradigms should operate under the assumption that truncation of αsyn is likely occurring in both initial and progressive disease stages, and preventing truncation may be an effective preventative strategy against pathologic inclusion formation.
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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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Esteves, A. R., D. M. Arduíno, D. F. F. Silva, C. R. Oliveira, and S. M. Cardoso. "Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD." Parkinson's Disease 2011 (2011): 1–20. http://dx.doi.org/10.4061/2011/693761.
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While the etiology of Parkinson's disease remains largely elusive, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in Parkinson's disease. Mitochondria are remarkably primed to play a vital role in neuronal cell survival since they are key regulators of energy metabolism (as ATP producers), of intracellular calcium homeostasis, of NAD+/NADH ratio, and of endogenous reactive oxygen species production and programmed cell death. In this paper, we focus on mitochondrial dysfunction-mediated alpha-synuclein aggregation. We highlight some of the findings that provide proof of evidence for a mitochondrial metabolism control in Parkinson's disease, namely, mitochondrial regulation of microtubule-dependent cellular traffic and autophagic lysosomal pathway. The knowledge that microtubule alterations may lead to autophagic deficiency and may compromise the cellular degradation mechanisms that culminate in the progressive accumulation of aberrant protein aggregates shields new insights to the way we address Parkinson's disease. In line with this knowledge, an innovative window for new therapeutic strategies aimed to restore microtubule network may be unlocked.
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Cheng, Jingjing, Qingqing Lu, Li Song, and Margaret S. Ho. "α-Synuclein Trafficking in Parkinson’s Disease: Insights From Fly and Mouse Models." ASN Neuro 10 (January 2018): 175909141881258. http://dx.doi.org/10.1177/1759091418812587.
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Protein aggregation and accumulation are common pathological hallmarks in neurodegenerative diseases. To efficiently clear and eliminate such aggregation becomes an important cellular strategy for cell survival. Lewy bodies inclusion and aggregation of α-Synuclein (α-Syn) during the pathogenesis of Parkinson’s disease (PD) serve as a good example and are potentially linked to other pathological PD features such as progressive dopaminergic neuron cell death, behavioral defects, and nonmotor symptoms like anosmia, cognitive impairment, and depression. Years of research have revealed a variety of mechanisms underlying α-Syn aggregation, clearance, and spread. Particularly, vesicular routes associated with the trafficking of α-Syn, leading to its aggregation and accumulation, have been shown to play vital roles in PD pathogenesis. How α-Syn proteins propagate among cells in a prion-like manner, either from or to neurons and glia, via means of uptake or secretion, are questions under active investigation and have been of central interest in the field of PD study. This review covers components and pathways of possible vesicular routes involved in α-Syn trafficking. Events including but not limited to exocytosis and endocytosis will be discussed within the context of an overall cellular trafficking theme. Recent advances on α-Syn trafficking mechanisms and their significance in mediating PD pathogenesis will be thoroughly reviewed, ending with a discussion on the advantages and limitations of different animal PD models.
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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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Folke, Jonas, Emil Bergholt, Bente Pakkenberg, Susana Aznar, and Tomasz Brudek. "Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson’s Disease." International Journal of Molecular Sciences 23, no. 12 (June 12, 2022): 6554. http://dx.doi.org/10.3390/ijms23126554.
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Multiple-system trophy (MSA) and Parkinson’s Disease (PD) are both progressive, neurodegenerative diseases characterized by neuropathological deposition of aggregated alpha-synuclein (αSyn). The causes behind this aggregation are still unknown. We have reported aberrancies in MSA and PD patients in naturally occurring autoantibodies (nAbs) against αSyn (anti-αSyn-nAbs), which are important partakers in anti-aggregatory processes, immune-mediated clearance, and anti-inflammatory functions. To elaborate further on the timeline of autoimmune aberrancies towards αSyn, we investigated here the Immunoglobulin (Ig) affinity profile and subclass composition (IgG-total, IgG1-4 and IgM) of anti-αSyn-nAbs in serum samples from prodromal (p) phases of MSA and PD. Using an electrochemiluminescence competition immunoassay, we confirmed that the repertoire of high-affinity anti-αSyn-nAbs is significantly reduced in pMSA and pPD. Further, we demonstrated that pPD had increased anti-αSyn IgG-total levels compared to pMSA and controls, concordant with increased anti-αSyn IgG1 levels in pPD. Anti-αSyn IgG2 and IgG4 levels were reduced in pMSA and pPD compared with controls, whereas anti-αSyn IgG3 levels were reduced in pMSA compared to pPD and controls. The results indicate that the impaired reactivity towards αSyn occurs prior to disease onset. The apparent lack of high-affinity anti-αSyn nAbs may result in reduced clearance of αSyn, leading to aggregation of the protein. Thus, this study provides novel insights into possible causes behind the pathogenesis in synucleinopathies such as MSA and PD.
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Cahill, Catherine M., Rozaleen Aleyadeh, Jin Gao, Changning Wang, and Jack T. Rogers. "Alpha-Synuclein in Alcohol Use Disorder, Connections with Parkinson’s Disease and Potential Therapeutic Role of 5’ Untranslated Region-Directed Small Molecules." Biomolecules 10, no. 10 (October 21, 2020): 1465. http://dx.doi.org/10.3390/biom10101465.
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Alpha-synuclein (α-Syn) is a 140-amino acid (aa) protein encoded by the Synuclein alpha SNCA gene. It is the synaptic protein associated with Parkinson’s disease (PD) and is the most highly expressed protein in the Lewy bodies associated with PD and other alpha synucleopathies, including Lewy body dementia (LBD) and multiple system atrophy (MSA). Iron deposits are present in the core of Lewy bodies, and there are reports suggesting that divalent metal ions including Cu2+ and Fe2+ enhance the aggregation of α-Syn. Differential expression of α-Syn is associated with alcohol use disorder (AUD), and specific genetic variants contribute to the risk for alcoholism, including alcohol craving. Spliced variants of α-Syn, leading to the expression of several shorter forms which are more prone to aggregation, are associated with both PD and AUD, and common transcript variants may be able to predict at-risk populations for some movement disorders or subtypes of PD, including secondary Parkinsonism. Both PD and AUD are associated with liver and brain iron dyshomeostasis. Research over the past decade has shown that α-Syn has iron import functions with an ability to oxidize the Fe3+ form of iron to Fe2+ to facilitate its entry into cells. Our prior research has identified an iron-responsive element (IRE) in the 5’ untranslated region (5’UTR) of α-Syn mRNA, and we have used the α-Syn 5’UTR to screen for small molecules that modulate its expression in the H4 neuronal cell line. These screens have led us to identify several interesting small molecules capable of both decreasing and increasing α-Syn expression and that may have the potential, together with the recently described mesenchymal stem cell therapies, to normalize α-Syn expression in different regions of the alcoholic and PD brain.
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Beekes, Michael. "The Neural Gut–Brain Axis of Pathological Protein Aggregation in Parkinson’s Disease and Its Counterpart in Peroral Prion Infections." Viruses 13, no. 7 (July 18, 2021): 1394. http://dx.doi.org/10.3390/v13071394.
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A neuropathological hallmark of Parkinson’s disease (PD) is the cerebral deposition of abnormally aggregated α-synuclein (αSyn). PD-associated αSyn (αSynPD) aggregates are assumed to act, in a prion-like manner, as proteinaceous nuclei (“seeds”) capable of self-templated propagation. Braak and colleagues put forward the idea of a neural gut-brain axis mediating the centripetal spread of αSynPD pathology from the enteric nervous system (ENS) to the brain in PD. This has sparked great interest and initiated passionate discussions both in support of and opposing the suggested hypothesis. A precedent for the spread of protein seeds or seeding from the gastro-intestinal (GI) tract to the central nervous system (CNS) had been previously revealed for pathological prion protein in peroral prion infections. This article scrutinizes the similarities and dissimilarities between the pathophysiological spread of disease-associated protein aggregation along the neural gut–brain axis in peroral prion infections and PD. On this basis, evidence supporting the proposed neural gut–brain axis in PD is concluded to be not as robust as that established for peroral prion infections. New tools for the ultrasensitive detection of αSynPD-associated seeding activity in archived or fresh human tissue samples such as real-time quaking induced conversion (RT-QuIC) or protein misfolding cyclic amplification (PMCA) assays can possibly help to address this deficit in the future.
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Näsström, Thomas, Jörgen Ådén, Fumina Shibata, Per Ola Andersson, and Björn C. G. Karlsson. "A Capped Peptide of the Aggregation Prone NAC 71–82 Amino Acid Stretch of α-Synuclein Folds into Soluble β-Sheet Oligomers at Low and Elevated Peptide Concentrations." International Journal of Molecular Sciences 21, no. 5 (February 27, 2020): 1629. http://dx.doi.org/10.3390/ijms21051629.
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Although Lewy bodies and Lewy neurites are hallmarks of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), misfolded α-synuclein oligomers are nowadays believed to be key for the development of these diseases. Attempts to target soluble misfolded species of the full-length protein have been limited so far, probably due to the fast aggregation kinetics and burial of aggregation prone segments in final cross-β-sheet fibrils. A previous characterisation study of fibrils prepared from a capped peptide of the non-amyloid β-component (NAC) 71–82 amino acid stretch of α-synuclein demonstrated an increased aggregation propensity resulting in a cross-β-structure that is also found in prion proteins. From this, it was suggested that capped NAC 71–82 peptide oligomers would provide interesting motifs with a capacity to regulate disease development. Here, we demonstrated, from a series of circular dichroism spectroscopic measurements and molecular dynamics simulations, the molecular-environment-sensitive behaviour of the capped NAC 71–82 peptide in a solution phase and the formation of β-sheet oligomeric structures in the supernatant of a fibrillisation mixture. These results highlighted the use of the capped NAC 71–82 peptide as a motif in the preparation of oligomeric β-sheet structures that potentially could be used in therapeutic strategies in the fight against progressive neurodegenerative disorders, such as PD and DLB.
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Yu, Kun-Hua, and Cheng-I. Lee. "Quercetin Disaggregates Prion Fibrils and Decreases Fibril-Induced Cytotoxicity and Oxidative Stress." Pharmaceutics 12, no. 11 (November 11, 2020): 1081. http://dx.doi.org/10.3390/pharmaceutics12111081.
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Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases caused by misfolding and aggregation of prion protein (PrP). Previous studies have demonstrated that quercetin can disaggregate some amyloid fibrils, such as amyloid β peptide (Aβ) and α-synuclein. However, the disaggregating ability is unclear in PrP fibrils. In this study, we examined the amyloid fibril-disaggregating activity of quercetin on mouse prion protein (moPrP) and characterized quercetin-bound moPrP fibrils by imaging, proteinase resistance, hemolysis assay, cell viability, and cellular oxidative stress measurements. The results showed that quercetin treatment can disaggregate moPrP fibrils and lead to the formation of the proteinase-sensitive amorphous aggregates. Furthermore, quercetin-bound fibrils can reduce the membrane disruption of erythrocytes. Consequently, quercetin-bound fibrils cause less oxidative stress, and are less cytotoxic to neuroblastoma cells. The role of quercetin is distinct from the typical function of antiamyloidogenic drugs that inhibit the formation of amyloid fibrils. This study provides a solution for the development of antiamyloidogenic therapy.
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Harischandra, Dilshan S., Dharmin Rokad, Matthew L. Neal, Shivani Ghaisas, Sireesha Manne, Souvarish Sarkar, Nikhil Panicker, et al. "Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein." Science Signaling 12, no. 572 (March 12, 2019): eaau4543. http://dx.doi.org/10.1126/scisignal.aau4543.
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The aggregation of α-synuclein (αSyn) is considered a key pathophysiological feature of certain neurodegenerative disorders, collectively termed synucleinopathies. Given that a prion-like, cell-to-cell transfer of misfolded αSyn has been recognized in the spreading of αSyn pathology in synucleinopathies, we investigated the biological mechanisms underlying the propagation of the disease with respect to environmental neurotoxic stress. Considering the potential role of the divalent metal manganese (Mn2+) in protein aggregation, we characterized its effect on αSyn misfolding and transmission in experimental models of Parkinson’s disease. In cultured dopaminergic neuronal cells stably expressing wild-type human αSyn, misfolded αSyn was secreted through exosomes into the extracellular medium upon Mn2+ exposure. These exosomes were endocytosed through caveolae into primary microglial cells, thereby mounting neuroinflammatory responses. Furthermore, Mn2+-elicited exosomes exerted a neurotoxic effect in a human dopaminergic neuronal model (LUHMES cells). Moreover, bimolecular fluorescence complementation (BiFC) analysis revealed that Mn2+ accelerated the cell-to-cell transmission of αSyn, resulting in dopaminergic neurotoxicity in a mouse model of Mn2+ exposure. Welders exposed to Mn2+ had increased misfolded αSyn content in their serum exosomes. Stereotaxically delivering αSyn-containing exosomes, isolated from Mn2+-treated αSyn-expressing cells, into the striatum initiated Parkinsonian-like pathological features in mice. Together, these results indicate that Mn2+ exposure promotes αSyn secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models.
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Munoz-Montesino, Carola, Christina Sizun, Mohammed Moudjou, Laetitia Herzog, Fabienne Reine, Jérôme Chapuis, Danica Ciric, et al. "Generating Bona Fide Mammalian Prions with Internal Deletions." Journal of Virology 90, no. 15 (May 25, 2016): 6963–75. http://dx.doi.org/10.1128/jvi.00555-16.
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ABSTRACTMammalian prions are PrP proteins with altered structures causing transmissible fatal neurodegenerative diseases. They are self-perpetuating through formation of beta-sheet-rich assemblies that seed conformational change of cellular PrP. Pathological PrP usually forms an insoluble protease-resistant core exhibiting beta-sheet structures but no more alpha-helical content, loosing the three alpha-helices contained in the correctly folded PrP. The lack of a high-resolution prion structure makes it difficult to understand the dynamics of conversion and to identify elements of the protein involved in this process. To determine whether completeness of residues within the protease-resistant domain is required for prions, we performed serial deletions in the helix H2 C terminus of ovine PrP, since this region has previously shown some tolerance to sequence changes without preventing prion replication. Deletions of either four or five residues essentially preserved the overall PrP structure and mutant PrP expressed in RK13 cells were efficiently converted into bona fide prions upon challenge by three different prion strains. Remarkably, deletions in PrP facilitated the replication of two strains that otherwise do not replicate in this cellular context. Prions with internal deletion were self-propagating andde novoinfectious for naive homologous and wild-type PrP-expressing cells. Moreover, they caused transmissible spongiform encephalopathies in mice, with similar biochemical signatures and neuropathologies other than the original strains. Prion convertibility and transfer of strain-specific information are thus preserved despite shortening of an alpha-helix in PrP and removal of residues within prions. These findings provide new insights into sequence/structure/infectivity relationship for prions.IMPORTANCEPrions are misfolded PrP proteins that convert the normal protein into a replicate of their own abnormal form. They are responsible for invariably fatal neurodegenerative disorders. Other aggregation-prone proteins appear to have a prion-like mode of expansion in brains, such as in Alzheimer's or Parkinson's diseases. To date, the resolution of prion structure remains elusive. Thus, to genetically define the landscape of regions critical for prion conversion, we tested the effect of short deletions. We found that, surprisingly, removal of a portion of PrP, the C terminus of alpha-helix H2, did not hamper prion formation but generated infectious agents with an internal deletion that showed characteristics essentially similar to those of original infecting strains. Thus, we demonstrate that completeness of the residues inside prions is not necessary for maintaining infectivity and the main strain-specific information, while reporting one of the few if not the only bona fide prions with an internal deletion.
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Bertsch, Uwe, Konstanze F. Winklhofer, Thomas Hirschberger, Jan Bieschke, Petra Weber, F. Ulrich Hartl, Paul Tavan, Jörg Tatzelt, Hans A. Kretzschmar, and Armin Giese. "Systematic Identification of Antiprion Drugs by High-Throughput Screening Based on Scanning for Intensely Fluorescent Targets." Journal of Virology 79, no. 12 (June 15, 2005): 7785–91. http://dx.doi.org/10.1128/jvi.79.12.7785-7791.2005.
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ABSTRACT Conformational changes and aggregation of specific proteins are hallmarks of a number of diseases, like Alzheimer's disease, Parkinson's disease, and prion diseases. In the case of prion diseases, the prion protein (PrP), a neuronal glycoprotein, undergoes a conformational change from the normal, mainly alpha-helical conformation to a disease-associated, mainly beta-sheeted scrapie isoform (PrPSc), which forms amyloid aggregates. This conversion, which is crucial for disease progression, depends on direct PrPC/PrPSc interaction. We developed a high-throughput assay based on scanning for intensely fluorescent targets (SIFT) for the identification of drugs which interfere with this interaction at the molecular level. Screening of a library of 10,000 drug-like compounds yielded 256 primary hits, 80 of which were confirmed by dose response curves with half-maximal inhibitory effects ranging from 0.3 to 60 μM. Among these, six compounds displayed an inhibitory effect on PrPSc propagation in scrapie-infected N2a cells. Four of these candidate drugs share an N′-benzylidene-benzohydrazide core structure. Thus, the combination of high-throughput in vitro assay with the established cell culture system provides a rapid and efficient method to identify new antiprion drugs, which corroborates that interaction of PrPC and PrPSc is a crucial molecular step in the propagation of prions. Moreover, SIFT-based screening may facilitate the search for drugs against other diseases linked to protein aggregation.
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Underwood, Rachel, Bing Wang, Christine Carico, Robert H. Whitaker, William J. Placzek, and Talene A. Yacoubian. "The GTPase Rab27b regulates the release, autophagic clearance, and toxicity of α-synuclein." Journal of Biological Chemistry 295, no. 23 (April 29, 2020): 8005–16. http://dx.doi.org/10.1074/jbc.ra120.013337.
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α-Synuclein (αsyn) is the primary component of proteinaceous aggregates termed Lewy bodies that pathologically define synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). αsyn is hypothesized to spread through the brain in a prion-like fashion by misfolded protein forming a template for aggregation of endogenous αsyn. The cell-to-cell release and uptake of αsyn are considered important processes for its prion-like spread. Rab27b is one of several GTPases essential to the endosomal-lysosomal pathway and is implicated in protein secretion and clearance, but its role in αsyn spread has yet to be characterized. In this study, we used a paracrine αsyn in vitro neuronal model to test the impact of Rab27b on αsyn release, clearance, and toxicity. shRNA-mediated knockdown (KD) of Rab27b increased αsyn-mediated paracrine toxicity. Rab27b reduced αsyn release primarily through nonexosomal pathways, but the αsyn released after Rab27b KD was of higher-molecular-weight species, as determined by size-exclusion chromatography. Rab27b KD increased intracellular levels of insoluble αsyn and led to an accumulation of endogenous light chain 3 (LC3)-positive puncta. Rab27b KD also decreased LC3 turnover after treatment with an autophagosome-lysosome fusion inhibitor, chloroquine, indicating that Rab27b KD induces a defect in autophagic flux. Rab27b protein levels were increased in brain lysates obtained from postmortem tissues of individuals with PD and DLB compared with healthy controls. These data indicate a role for Rab27b in the release, clearance, and toxicity of αsyn and, ultimately, in the pathogenesis of synucleinopathies.
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Miraglia, Fabiana, and Emanuela Colla. "Microbiome, Parkinson’s Disease and Molecular Mimicry." Cells 8, no. 3 (March 7, 2019): 222. http://dx.doi.org/10.3390/cells8030222.
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Parkinson’s Disease (PD) is typically classified as a neurodegenerative disease affecting the motor system. Recent evidence, however, has uncovered the presence of Lewy bodies in locations outside the CNS, in direct contact with the external environment, including the olfactory bulbs and the enteric nervous system. This, combined with the ability of alpha-synuclein (αS) to propagate in a prion-like manner, has supported the hypothesis that the resident microbial community, commonly referred to as microbiota, might play a causative role in the development of PD. In this article, we will be reviewing current knowledge on the importance of the microbiota in PD pathology, concentrating our investigation on mechanisms of microbiota-host interactions that might become harmful and favor the onset of PD. Such processes, which include the secretion of bacterial amyloid proteins or other metabolites, may influence the aggregation propensity of αS directly or indirectly, for example by favoring a pro-inflammatory environment in the gut. Thus, while the development of PD has not yet being associated with a unique microbial species, more data will be necessary to examine potential harmful interactions between the microbiota and the host, and to understand their relevance in PD pathogenesis.
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Uçar, Buket, Nadia Stefanova, and Christian Humpel. "Spreading of Aggregated α-Synuclein in Sagittal Organotypic Mouse Brain Slices." Biomolecules 12, no. 2 (January 19, 2022): 163. http://dx.doi.org/10.3390/biom12020163.
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The accumulation of α-synuclein (α-syn) in the brain plays a role in synucleinopathies and it is hypothesized to spread in a prion-like fashion between connected brain regions. In the present study, we aim to investigate this spreading in well-characterized sagittal organotypic whole brain slices taken from postnatal wild type (WT) and transgenic mice overexpressing human α-syn under the promoter of proteolipid protein (PLP). Collagen hydrogels were loaded with monomers of human α-syn, as well as human and mouse pre-formed fibrils (PFFs), to allow local application and slow release. The spreading of α-syn was evaluated in different brain regions by immunohistochemistry for total α-syn and α-syn phosphorylated at the serine129 position (α-syn-P). The application of human and mouse PFFs of α-syn caused the aggregation and spreading of α-syn-P in the brain slices, which was pronounced the most at the region of hydrogel application and surrounding striatum, as well as along the median forebrain bundle. The organotypic slices from transgenic mice showed significantly more α-syn pathology than those from WT mice. The present study demonstrates that seeding with α-syn PFFs but not monomers induced intracellular α-syn pathology, which was significantly more prominent in brain slices with α-syn overexpression. This is consistent with the prion-like spreading theory of α-syn aggregates. The sagittal whole brain slices characterized in this study carry the potential to be used as a novel model to study α-syn pathology.
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Lashuel, Hilal A., and Peter T. Lansbury. "Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?" Quarterly Reviews of Biophysics 39, no. 2 (May 2006): 167–201. http://dx.doi.org/10.1017/s0033583506004422.
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1. Introduction 22. What is the significance of the shared structural properties of disease-associated protein fibrils? 32.1 Mechanism of amyloid fibril formation in vitro 62.1.1 In vitro fibril formation involves transient population of ordered aggregates of intermediate stability, or protofibrils 63. Toxic properties of protofibrils 73.1 Protofibrils, rather than fibrils, are likely to be pathogenic 73.2 The toxic protofibril may be a mixture of related species 83.3 Morphological similarities of protofibrils suggest a common mechanism of toxicity 93.4 Are the amyloid diseases a subset of a much larger class of previously unrecognized protofibril diseases? 93.5 Fibrils, in the form of aggresomes, may function to sequester toxic protofibrils 94. Amyloid pores, a common structural link among protein aggregation neurodegenerative diseases 104.1 Mechanistic studies of amyloid fibril formation reveal common features, including pore-like protofibrils 104.1.1 Amyloid-β (Aβ) (Alzheimer's disease) 104.1.2 α-Synuclein (PD and diffuse Lewy body disease) 124.1.3 ABri (familial British dementia) 134.1.4 Superoxide dismutase-1 (amyotrophic lateral sclerosis) 134.1.5 Prion protein (Creutzfeldt–Jakob disease, bovine spongiform encephalopathy, etc.) 144.1.6 Huntingtin (Huntington's disease) 144.2 Amyloidogenic proteins that are not linked to disease also from pore-like protofibrils 154.3 Amyloid proteins form non-fibrillar aggregates that have properties of protein channels or pores 154.3.1 Aβ ‘channels’ 154.3.2 α-Synuclein ‘pores’ 164.3.3 PrP ‘channels’ 164.3.4 Polyglutamine ‘channels’ 174.4 Nature uses β-strand-mediated protein oligomerization to construct pore-forming toxins 175. Mechanisms of protofibril induced toxicity in protein aggregation diseases 195.1 The amyloid pore can explain the age-association and cell-type selectivity of the neurodegenerative diseases 195.2 Protofibrils may promote their own accumulation by inhibiting the proteasome 206. Testing the amyloid pore hypothesis by attempting to disprove it 217. Acknowledgments 228. References 22Protein fibrillization is implicated in the pathogenesis of most, if not all, age-associated neurodegenerative diseases, but the mechanism(s) by which it triggers neuronal death is unknown. Reductionist in vitro studies suggest that the amyloid protofibril may be the toxic species and that it may amplify itself by inhibiting proteasome-dependent protein degradation. Although its pathogenic target has not been identified, the properties of the protofibril suggest that neurons could be killed by unregulated membrane permeabilization, possibly by a type of protofibril referred to here as the ‘amyloid pore’. The purpose of this review is to summarize the existing supportive circumstantial evidence and to stimulate further studies designed to test the validity of this hypothesis.
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Mikalauskaite, Kamile, Mantas Ziaunys, Tomas Sneideris, and Vytautas Smirnovas. "Effect of Ionic Strength on Thioflavin-T Affinity to Amyloid Fibrils and Its Fluorescence Intensity." International Journal of Molecular Sciences 21, no. 23 (November 24, 2020): 8916. http://dx.doi.org/10.3390/ijms21238916.
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The formation of amyloid fibrils is linked to multiple neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Despite years of research and countless studies on the topic of such aggregate formation, as well as their resulting structure, the current knowledge is still fairly limited. One of the main aspects prohibiting effective aggregation tracking is the environment’s effect on amyloid-specific dyes, namely thioflavin-T (ThT). Currently, there are only a few studies hinting at ionic strength being one of the factors that modulate the dye’s binding affinity and fluorescence intensity. In this work we explore this effect under a range of ionic strength conditions, using insulin, lysozyme, mouse prion protein, and α-synuclein fibrils. We show that ionic strength is an extremely important factor affecting both the binding affinity, as well as the fluorescence intensity of ThT.
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Allsop, David, Jennifer Mayes, Susan Moore, Atef Masad, and Brian J. Tabner. "Metal-dependent generation of reactive oxygen species from amyloid proteins implicated in neurodegenerative disease." Biochemical Society Transactions 36, no. 6 (November 19, 2008): 1293–98. http://dx.doi.org/10.1042/bst0361293.
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Using a method based on ESR spectroscopy and spin-trapping, we have shown that Aβ (amyloid β-peptide) (implicated in Alzheimer's disease), α-synuclein (implicated in Parkinson's disease), ABri (British dementia peptide) (responsible for familial British dementia), certain toxic fragments of the prion protein (implicated in the transmissible spongiform encephalopathies) and the amylin peptide (found in the pancreas in Type 2 diabetes mellitus) all have the common ability to generate H2O2in vitro. Numerous controls (reverse, scrambled and non-toxic peptides) lacked this property. We have also noted a positive correlation between the ability of the various proteins tested to generate H2O2 and their toxic effects on cultured cells. In the case of Aβ and ABri, we have shown that H2O2 is generated as a short burst during the early stages of aggregation and is associated with the presence of protofibrils or oligomers, rather than mature fibrils. H2O2 is readily converted into the aggressive hydroxyl radical by Fenton chemistry, and this extremely reactive radical could be responsible for much of the oxidative damage seen in all of the above disorders. We suggest that the formation of a redox-active complex involving the relevant amyloidogenic protein and certain transition-metal ions could play an important role in the pathogenesis of several different protein misfolding disorders.
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Atrian, Sílvia, and Mercè Capdevila. "Metallothionein-protein interactions." BioMolecular Concepts 4, no. 2 (April 1, 2013): 143–60. http://dx.doi.org/10.1515/bmc-2012-0049.
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AbstractMetallothioneins (MTs) are a family of universal, small proteins, sharing a high cysteine content and an optimal capacity for metal ion coordination. They take part in a plethora of metal ion-related events (from detoxification to homeostasis, storage, and delivery), in a wide range of stress responses, and in different pathological processes (tumorigenesis, neurodegeneration, and inflammation). The information on both intracellular and extracellular interactions of MTs with other proteins is here comprehensively reviewed. In mammalian kidney, MT1/MT2 interact with megalin and related receptors, and with the transporter transthyretin. Most of the mammalian MT partners identified concern interactions with central nervous system (mainly brain) proteins, both through physical contact or metal exchange reactions. Physical interactions mainly involve neuronal secretion multimers. Regarding metal swap events, brain MT3 appears to control the metal ion load in peptides whose aggregation leads to neurodegenerative disorders, such as Aβ peptide, α-synuclein, and prion proteins (Alzheimer’s and Parkinson’s diseases, and spongiform encephalopathies, respectively). Interaction with ferritin and bovine serum albumin are also documented. The intercourse of MTs with zinc-dependent enzymes and transcription factors is capable to activate/deactivate them, thus conferring MTs the role of metabolic and gene expression regulators. As some of these proteins are involved in cell cycle and proliferation control (p53, nuclear factor κB, and PKCμ), they are considered in the context of oncogenesis and tumor progression. Only one non-mammalian MT interaction, involving Drosophila MtnA and MtnB major isoforms and peroxiredoxins, has been reported. The prospective use for biomedical applications of the MT-interaction information is finally discussed.
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Kumar, Jatish, Hasier Eraña, Elena López-Martínez, Nathalie Claes, Víctor F. Martín, Diego M. Solís, Sara Bals, Aitziber L. Cortajarena, Joaquín Castilla, and Luis M. Liz-Marzán. "Detection of amyloid fibrils in Parkinson’s disease using plasmonic chirality." Proceedings of the National Academy of Sciences 115, no. 13 (March 12, 2018): 3225–30. http://dx.doi.org/10.1073/pnas.1721690115.
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Amyloid fibrils, which are closely associated with various neurodegenerative diseases, are the final products in many protein aggregation pathways. The identification of fibrils at low concentration is, therefore, pivotal in disease diagnosis and development of therapeutic strategies. We report a methodology for the specific identification of amyloid fibrils using chiroptical effects in plasmonic nanoparticles. The formation of amyloid fibrils based on α-synuclein was probed using gold nanorods, which showed no apparent interaction with monomeric proteins but effective adsorption onto fibril structures via noncovalent interactions. The amyloid structure drives a helical nanorod arrangement, resulting in intense optical activity at the surface plasmon resonance wavelengths. This sensing technique was successfully applied to human brain homogenates of patients affected by Parkinson’s disease, wherein protein fibrils related to the disease were identified through chiral signals from Au nanorods in the visible and near IR, whereas healthy brain samples did not exhibit any meaningful optical activity. The technique was additionally extended to the specific detection of infectious amyloids formed by prion proteins, thereby confirming the wide potential of the technique. The intense chiral response driven by strong dipolar coupling in helical Au nanorod arrangements allowed us to detect amyloid fibrils down to nanomolar concentrations.
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Meiliana, Anna, Nurrani Mustika Dewi, and Andi Wijaya. "New Insight in The Molecular Mechanisms of Neurodegenerative Disease." Indonesian Biomedical Journal 10, no. 1 (April 29, 2018): 16. http://dx.doi.org/10.18585/inabj.v10i1.448.
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BACKGROUND: Redox and proteotoxic stress contributes to age-dependent accumulation of dysfunctional mitochondria and protein aggregates, and is associated with neurodegeneration. The free radical theory of aging inspired many studies using reactive species scavengers such as alpha-tocopherol, ascorbate and coenzyme-Q to suppress the initiation of oxidative stress. However, clinical trials have had limited success in the treatment of neurodegenerative diseases (NDDs).CONTENT: The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of NDDs. In Alzheimer’s disease, the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optica lmicroscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism, corruptive protein templating. The accumulation of redox modified proteins or organelles cannot be reversed by oxidant intercepting antioxidants and must then be removed by alternative mechanisms. Autophagy serves this essential function in removing damaged or dysfunctional proteins and organelles thus preserving neuronal function and survival.SUMMARY: Senescent cells and their senescence-associated secretory phenotypes (SASPs) may constitute a novel, understudied, and potentially important contributor to neuro-inflammation and subsequent neurodegeneration. Characterization of cellular senescence in the brain could uncover novel therapeutic targets for the prevention and treatment of chronic age-related NDDs.KEYWORDS: brain, aging, neurodegeneration, DNA damage, senescence, neuro-inflammation, mitochondria, lysosome, proteostasis, prion, amyloidosis
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Hardy, J. "Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: ‘permissive templating’ as a general mechanism underlying neurodegeneration." Biochemical Society Transactions 33, no. 4 (August 1, 2005): 578–81. http://dx.doi.org/10.1042/bst0330578.
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Loci underlying autosomal dominant forms of most neurodegenerative disease have been identified: prion mutations cause Gerstmann Straussler syndrome and hereditary Creutzfeldt–Jakob disease, tau mutations cause autosomal dominant frontal temporal dementia and α-synuclein mutations cause autosomal dominant Parkinson's disease. In these cases, the pathogenic mutation is in the protein that is deposited in the diseased tissue and the whole protein is deposited. In Alzheimer's disease, mutations in amyloid precursor protein or in the presenilins cause autosomal dominant disease. These are the substrate and proteases responsible for the production of the deposited peptide Aβ. Thus, in all the cases, the mutations lead to the disease by a mechanism that involves the deposition process. Furthermore, sporadic forms of all these diseases are predisposed by genetic variability at the same loci, implying that the quantity of the normal protein influences the risk of this form of disease. These results show that the amount of pathogenic protein expression is a key factor in determining disease initiation. Recent work on transgenic models of these diseases is consistent with the view that there are two stages of pathogenesis: a concentration-dependent formation of a pathogenic protein oligomer followed by aggregation on to this oligomeric template by a process that is less dependent on the concentration of the protein.
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Shen, Ning, Ge Song, Haiqiang Yang, Xiaoyang Lin, Breanna Brown, Yuzhu Hong, Jianfeng Cai, and Chuanhai Cao. "Identifying the Pathological Domain of Alpha- Synuclein as a Therapeutic for Parkinson’s Disease." International Journal of Molecular Sciences 20, no. 9 (May 11, 2019): 2338. http://dx.doi.org/10.3390/ijms20092338.
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Alpha-synuclein is considered the major pathological protein associated with Parkinson’s disease, but there is still no effective immunotherapy which targets alpha-synuclein. In order to create a safer and more effective therapy against PD, we are targeting an epitope of alpha-synuclein rather than full-length alpha-synuclein. We have selected several antigenic domains (B-cell epitope) through antigenicity prediction, and also made several recombinant protein fragments from alpha-synuclein upon antigenicity prediction in an E. coli system. We then tested the function of each of the peptides and recombinant fragments in aggregation, their toxicity and antigenicity. We have discovered that the full-length recombinant (aa1–140) can aggregate into oligomers or even fibrils, and fragment aa15–65 can promote the aggregation of aa1–140. It is worth noting that it not only promotes whole protein aggregation, but also self-aggregates as seen by western blotting and silver staining assays. We have tested all candidates on primary neurons for their toxicity and discovered that aa15–65 is the most toxic domain compared to all other fragments. The antibody targeting this domain also showed both anti-aggregation activity and some therapeutic effect. Therefore, we believe that we have identified the most potent therapeutic domain of alpha synuclein as a therapeutic target.
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Labrie, Viviane, and Patrik Brundin. "Alpha-Synuclein to the Rescue: Immune Cell Recruitment by Alpha-Synuclein during Gastrointestinal Infection." Journal of Innate Immunity 9, no. 5 (2017): 437–40. http://dx.doi.org/10.1159/000479653.
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Intraneuronal accumulation of misfolded alpha-synuclein in the central and peripheral nervous systems is strongly linked to Parkinson disease (PD) and other related synucleinopathies. In rare inherited forms of PD, point mutations or gene multiplications mediate the formation of alpha-synuclein protein aggregates. However, in most PD cases it is presumed that the combined effects of ageing and environmental factors drive the formation of alpha-synuclein aggregates. Despite advances regarding alpha-synuclein pathobiology, the normal functions of this protein and factors that regulate its expression are not well understood. We discuss a recent study reporting that viral infection induces alpha-synuclein expression in neurons of the gastrointestinal tract. Alpha-synuclein levels increased during norovirus infection in the duodenum of children. In an in vitro paradigm, monomeric and oligomeric alpha-synuclein acted as chemoattractants for neutrophils and monocytes, and promoted the maturation of dendritic cells. This suggests that alpha-synuclein facilitates immune responses to infection. We explore the possibility that intestinal infections, and associated inflammation, place individuals at increased risk of PD by increasing alpha-synuclein levels and promoting the formation of alpha-synuclein aggregates that propagate in a prion-like fashion via the vagal nerve to the brainstem.
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Toleikis, Zigmantas, Mantas Ziaunys, Lina Baranauskiene, Vytautas Petrauskas, Kristaps Jaudzems, and Vytautas Smirnovas. "S100A9 Alters the Pathway of Alpha-Synuclein Amyloid Aggregation." International Journal of Molecular Sciences 22, no. 15 (July 26, 2021): 7972. http://dx.doi.org/10.3390/ijms22157972.
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The formation of amyloid fibril plaques in the brain creates inflammation and neuron death. This process is observed in neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Alpha-synuclein is the main protein found in neuronal inclusions of patients who have suffered from Parkinson’s disease. S100A9 is a calcium-binding, pro-inflammation protein, which is also found in such amyloid plaques. To understand the influence of S100A9 on the aggregation of α-synuclein, we analyzed their co-aggregation kinetics and the resulting amyloid fibril structure by Fourier-transform infrared spectroscopy and atomic force microscopy. We found that the presence of S100A9 alters the aggregation kinetics of α-synuclein and stabilizes the formation of a particular amyloid fibril structure. We also show that the solution’s ionic strength influences the interplay between S100A9 and α-synuclein, stabilizing a different structure of α-synuclein fibrils.
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Ziaunys, Mantas, Andrius Sakalauskas, Kamile Mikalauskaite, and Vytautas Smirnovas. "Polymorphism of Alpha-Synuclein Amyloid Fibrils Depends on Ionic Strength and Protein Concentration." International Journal of Molecular Sciences 22, no. 22 (November 17, 2021): 12382. http://dx.doi.org/10.3390/ijms222212382.
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Protein aggregate formation is linked with multiple amyloidoses, including Alzheimer‘s and Parkinson‘s diseases. Currently, the understanding of such fibrillar structure formation and propagation is still not sufficient, the outcome of which is a lack of potent, anti-amyloid drugs. The environmental conditions used during in vitro protein aggregation assays play an important role in determining both the aggregation kinetic parameters, as well as resulting fibril structure. In the case of alpha-synuclein, ionic strength has been shown as a crucial factor in its amyloid aggregation. In this work, we examine a large sample size of alpha-synuclein aggregation reactions under thirty different ionic strength and protein concentration combinations and determine the resulting fibril structural variations using their dye-binding properties, secondary structure and morphology. We show that both ionic strength and protein concentration determine the structural variability of alpha-synuclein amyloid fibrils and that sometimes even identical conditions can result in up to four distinct types of aggregates.
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ANDREKOPOULOS, Christopher, Hao ZHANG, Joy JOSEPH, Shasi KALIVENDI, and B. KALYANARAMAN. "Bicarbonate enhances alpha-synuclein oligomerization and nitration: intermediacy of carbonate radical anion and nitrogen dioxide radical." Biochemical Journal 378, no. 2 (March 1, 2004): 435–47. http://dx.doi.org/10.1042/bj20031466.
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α-Synuclein, a neuronal presynaptic protein, has been reported to undergo oligomerization to form toxic Lewy bodies in neurodegenerative disorders. One of the proposed mechanisms for aggregation of α-synuclein involves oxidative and nitrative modifications. In the present study, we show that addition of 3-morpholino-sydnonimine chloride (SIN-1) or slow infusion of pre-formed peroxynitrite (ONOO−) to mixtures containing α-synuclein and HCO3− markedly enhanced both nitration and aggregation of α-synuclein through dityrosine formation. Bicarbonate-dependent peroxidase activity of Cu,Zn-superoxide dismutase (SOD1) also induced covalent aggregation of α-synuclein via a CO3•−-dependent mechanism. Nitrone spin traps completely inhibited CO3•−-mediated oxidation/nitration and aggregation of α-synuclein. Conversely, α-synuclein inhibited CO3•−-induced spin adduct formation. Independent evidence for CO3•−-mediated oxidation and dimerization of α-synuclein was obtained from UV photolysis of [(NH3)5CoCO3]+, which generates authentic CO3•−. Irradiation of [(NH3)5CoCO3]+ and NO2− in the presence of α-synuclein yielded nitration and aggregation products that were similar to those obtained from a SIN-1 (or slowly infused ONOO−) and HCO3− or a myeloperoxidase/H2O2/NO2− system. Hydrophobic membranes greatly influenced α-synuclein aggregation and nitration in these systems. We conclude that both CO3•− and NO2• could play a major role in the nitration/aggregation of α-synuclein.
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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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Kondratyev, Maxim S., Vladimir R. Rudnev, Kirill S. Nikolsky, Denis V. Petrovsky, Liudmila I. Kulikova, Kristina A. Malsagova, Alexander A. Stepanov, Arthur T. Kopylov, and Anna L. Kaysheva. "In Silico Study of the Interactions of Anle138b Isomer, an Inhibitor of Amyloid Aggregation, with Partner Proteins." International Journal of Molecular Sciences 23, no. 24 (December 17, 2022): 16096. http://dx.doi.org/10.3390/ijms232416096.
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Herein, we aimed to highlight current “gaps” in the understanding of the potential interactions between the Anle138b isomer ligand, a promising agent for clinical research, and the intrinsically disordered alpha-synuclein protein. The presence of extensive unstructured areas in alpha-synuclein determines its existence in the cell of partner proteins, including the cyclophilin A chaperone, which prevents the aggregation of alpha-synuclein molecules that are destructive to cell life. Using flexible and cascaded molecular docking techniques, we aimed to expand our understanding of the molecular architecture of the protein complex between alpha-synuclein, cyclophilin A and the Anle138b isomer ligand. We demonstrated the possibility of intricate complex formation under cellular conditions and revealed that the main interactions that stabilize the complex are hydrophobic and involve hydrogen.
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Xu, Lingjia, and Jiali Pu. "Alpha-Synuclein in Parkinson’s Disease: From Pathogenetic Dysfunction to Potential Clinical Application." Parkinson's Disease 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/1720621.
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Parkinson’s disease is a neurodegenerative disease/synucleinopathy that develops slowly; however, there is no efficient method of early diagnosis, nor is there a cure. Progressive dopaminergic neuronal cell loss in the substantia nigra pars compacta and widespread aggregation of theα-synuclein protein (encoded by theSNCAgene) in the form of Lewy bodies and Lewy neurites are the neuropathological hallmarks of Parkinson’s disease. TheSNCAgene has undergone gene duplications, triplications, and point mutations. However, the specific mechanism ofα-synuclein in Parkinson’s disease remains obscure. Recent research showed that variousα-synuclein oligomers, pathological aggregation, and propagation appear to be harmful in certain areas in Parkinson’s disease patients. This review summarizes our current knowledge of the pathogenetic dysfunction ofα-synuclein associated with Parkinson’s disease and highlights current approaches that seek to develop this protein as a possible diagnostic biomarker and therapeutic target.