Relevant bibliographies by topics / Α-synuclein aggregation

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  2. Dissertations / Theses
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Academic literature on the topic 'Α-synuclein aggregation'

Author: Grafiati
Published: 5 March 2024

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Journal articles on the topic "Α-synuclein aggregation"

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Surguchov, Andrei, and Alexei Surguchev. "Synucleins: New Data on Misfolding, Aggregation and Role in Diseases." Biomedicines 10, no. 12 (December 13, 2022): 3241. http://dx.doi.org/10.3390/biomedicines10123241.

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The synucleins are a family of natively unfolded (or intrinsically unstructured) proteins consisting of α-, β-, and γ-synuclein involved in neurodegenerative diseases and cancer. The current number of publications on synucleins has exceeded 16.000. They remain the subject of constant interest for over 35 years. Two reasons explain this unchanging attention: synuclein’s association with several severe human diseases and the lack of understanding of the functional roles under normal physiological conditions. We analyzed recent publications to look at the main trends and developments in synuclein research and discuss possible future directions. Traditional areas of peak research interest which still remain high among last year’s publications are comparative studies of structural features as well as functional research on of three members of the synuclein family. Another popular research topic in the area is a mechanism of α-synuclein accumulation, aggregation, and fibrillation. Exciting fast-growing area of recent research is α-synuclein and epigenetics. We do not present here a broad and comprehensive review of all directions of studies but summarize only the most significant recent findings relevant to these topics and outline potential future directions.
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Ham, Sangwoo, Seung Pil Yun, Hyojung Kim, Donghoon Kim, Bo Am Seo, Heejeong Kim, Jeong-Yong Shin, et al. "Amyloid-like oligomerization of AIMP2 contributes to α-synuclein interaction and Lewy-like inclusion." Science Translational Medicine 12, no. 569 (November 11, 2020): eaax0091. http://dx.doi.org/10.1126/scitranslmed.aax0091.

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Lewy bodies are pathological protein inclusions present in the brain of patients with Parkinson’s disease (PD). These inclusions consist mainly of α-synuclein with associated proteins, such as parkin and its substrate aminoacyl transfer RNA synthetase complex–interacting multifunctional protein-2 (AIMP2). Although AIMP2 has been suggested to be toxic to dopamine neurons, its roles in α-synuclein aggregation and PD pathogenesis are largely unknown. Here, we found that AIMP2 exhibits a self-aggregating property. The AIMP2 aggregate serves as a seed to increase α-synuclein aggregation via specific and direct binding to the α-synuclein monomer. The coexpression of AIMP2 and α-synuclein in cell cultures and in vivo resulted in the rapid formation of α-synuclein aggregates with a corresponding increase in toxicity. Moreover, accumulated AIMP2 in mouse brain was largely redistributed to insoluble fractions, correlating with the α-synuclein pathology. Last, we found that α-synuclein preformed fibril (PFF) seeding, adult Parkin deletion, or oxidative stress triggered a redistribution of both AIMP2 and α-synuclein into insoluble fraction in cells and in vivo. Supporting the pathogenic role of AIMP2, AIMP2 knockdown ameliorated the α-synuclein aggregation and dopaminergic cell death in response to PFF or 6-hydroxydopamine treatment. Together, our results suggest that AIMP2 plays a pathological role in the aggregation of α-synuclein in mice. Because AIMP2 insolubility and coaggregation with α-synuclein have been seen in the PD Lewy body, targeting pathologic AIMP2 aggregation might be useful as a therapeutic strategy for neurodegenerative α-synucleinopathies.
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Galvagnion, Céline, James W. P. Brown, Myriam M. Ouberai, Patrick Flagmeier, Michele Vendruscolo, Alexander K. Buell, Emma Sparr, and Christopher M. Dobson. "Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of α-synuclein." Proceedings of the National Academy of Sciences 113, no. 26 (June 13, 2016): 7065–70. http://dx.doi.org/10.1073/pnas.1601899113.

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Intracellular α-synuclein deposits, known as Lewy bodies, have been linked to a range of neurodegenerative disorders, including Parkinson’s disease. α-Synuclein binds to synthetic and biological lipids, and this interaction has been shown to play a crucial role for both α-synuclein’s native function, including synaptic plasticity, and the initiation of its aggregation. Here, we describe the interplay between the lipid properties and the lipid binding and aggregation propensity of α-synuclein. In particular, we have observed that the binding of α-synuclein to model membranes is much stronger when the latter is in the fluid rather than the gel phase, and that this binding induces a segregation of the lipids into protein-poor and protein-rich populations. In addition, α-synuclein was found to aggregate at detectable rates only when interacting with membranes composed of the most soluble lipids investigated here. Overall, our results show that the chemical properties of lipids determine whether or not the lipids can trigger the aggregation of α-synuclein, thus affecting the balance between functional and aberrant behavior of the protein.
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Hashimoto, Makoto, Edward Rockenstein, Michael Mante, Margaret Mallory, and Eliezer Masliah. "β-Synuclein Inhibits α-Synuclein Aggregation." Neuron 32, no. 2 (October 2001): 213–23. http://dx.doi.org/10.1016/s0896-6273(01)00462-7.

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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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Rott, Ruth, Raymonde Szargel, Vered Shani, Haya Hamza, Mor Savyon, Fatimah Abd Elghani, Rina Bandopadhyay, and Simone Engelender. "SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation." Proceedings of the National Academy of Sciences 114, no. 50 (November 27, 2017): 13176–81. http://dx.doi.org/10.1073/pnas.1704351114.

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α-Synuclein accumulation is a pathological hallmark of Parkinson’s disease (PD). Ubiquitinated α-synuclein is targeted to proteasomal or lysosomal degradation. Here, we identify SUMOylation as a major mechanism that counteracts ubiquitination by different E3 ubiquitin ligases and regulates α-synuclein degradation. We report that PIAS2 promotes SUMOylation of α-synuclein, leading to a decrease in α-synuclein ubiquitination by SIAH and Nedd4 ubiquitin ligases, and causing its accumulation and aggregation into inclusions. This was associated with an increase in α-synuclein release from the cells. A SUMO E1 inhibitor, ginkgolic acid, decreases α-synuclein levels by relieving the inhibition exerted on α-synuclein proteasomal degradation. α-Synuclein disease mutants are more SUMOylated compared with the wild-type protein, and this is associated with increased aggregation and inclusion formation. We detected a marked increase in PIAS2 expression along with SUMOylated α-synuclein in PD brains, providing a causal mechanism underlying the up-regulation of α-synuclein SUMOylation in the disease. We also found a significant proportion of Lewy bodies in nigral neurons containing SUMO1 and PIAS2. Our observations suggest that SUMOylation of α-synuclein by PIAS2 promotes α-synuclein aggregation by two mutually reinforcing mechanisms. First, it has a direct proaggregatory effect on α-synuclein. Second, SUMOylation facilitates α-synuclein aggregation by blocking its ubiquitin-dependent degradation pathways and promoting its accumulation. Therefore, inhibitors of α-synuclein SUMOylation provide a strategy to reduce α-synuclein levels and possibly aggregation in PD.
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Estaun-Panzano, Juan, Marie-Laure Arotcarena, and Erwan Bezard. "Monitoring α-synuclein aggregation." Neurobiology of Disease 176 (January 2023): 105966. http://dx.doi.org/10.1016/j.nbd.2022.105966.

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Caló, Laura, Eric Hidari, Michal Wegrzynowicz, Jeffrey W. Dalley, Bernard L. Schneider, Martyna Podgajna, Oleg Anichtchik, Emma Carlson, David Klenerman, and Maria Grazia Spillantini. "CSPα reduces aggregates and rescues striatal dopamine release in α-synuclein transgenic mice." Brain 144, no. 6 (March 24, 2021): 1661–69. http://dx.doi.org/10.1093/brain/awab076.

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Abstract α-Synuclein aggregation at the synapse is an early event in Parkinson’s disease and is associated with impaired striatal synaptic function and dopaminergic neuronal death. The cysteine string protein (CSPα) and α-synuclein have partially overlapping roles in maintaining synaptic function and mutations in each cause neurodegenerative diseases. CSPα is a member of the DNAJ/HSP40 family of co-chaperones and like α-synuclein, chaperones the SNARE complex assembly and controls neurotransmitter release. α-Synuclein can rescue neurodegeneration in CSPαKO mice. However, whether α-synuclein aggregation alters CSPα expression and function is unknown. Here we show that α-synuclein aggregation at the synapse is associated with a decrease in synaptic CSPα and a reduction in the complexes that CSPα forms with HSC70 and STGa. We further show that viral delivery of CSPα rescues in vitro the impaired vesicle recycling in PC12 cells with α-synuclein aggregates and in vivo reduces synaptic α-synuclein aggregates increasing monomeric α-synuclein and restoring normal dopamine release in 1-120hαSyn mice. These novel findings reveal a mechanism by which α-synuclein aggregation alters CSPα at the synapse, and show that CSPα rescues α-synuclein aggregation-related phenotype in 1-120hαSyn mice similar to the effect of α-synuclein in CSPαKO mice. These results implicate CSPα as a potential therapeutic target for the treatment of early-stage Parkinson’s disease.
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JENSEN, Poul H., Peter HØJRUP, Henrik HAGER, Morten S. NIELSEN, Linda JACOBSEN, Ole F. OLESEN, Jørgen GLIEMANN, and Ross JAKES. "Binding of Aβ to α- and β-synucleins: identification of segments in α-synuclein/NAC precursor that bind Aβ and NAC." Biochemical Journal 323, no. 2 (April 15, 1997): 539–46. http://dx.doi.org/10.1042/bj3230539.

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NAC, a 35-residue peptide derived from the neuronal protein α-synuclein/NAC precursor, is tightly associated with Aβ fibrils in Alzheimer's disease amyloid, and α-synuclein has recently been shown to bind Aβ in vitro. We have studied the interaction between Aβ and synucleins, aiming at determining segments in α-synuclein that can account for the binding, as well as identifying a possible interaction between Aβ and the β-type synuclein. We report that Aβ binds to native and recombinant α-synuclein, and to β-synuclein in an SDS-sensitive interaction (IC50 approx. 20 μM), as determined by chemical cross-linking and solid-phase binding assays. α-Synuclein and β-synuclein were found to stimulate Aβ-aggregation in vitro to the same extent. The synucleins also displayed Aβ-inhibitable binding of NAC and they were capable of forming dimers. Using proteolytic fragmentation of α-synuclein and cross-linking to 125I-Aβ, we identified two consecutive binding domains (residues 1–56 and 57–97) by Edman degradation and mass spectrometric analysis, and a synthetic peptide comprising residues 32–57 possessed Aβ-binding activity. To test further the possible significance in pathology, α-synuclein was biotinylated and shown to bind specifically to amyloid plaques in a brain with Alzheimer's disease. It is proposed that the multiple Aβ-binding sites in α-synuclein are involved in the development of amyloid plaques.
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Krumova, Petranka, Erik Meulmeester, Manuel Garrido, Marilyn Tirard, He-Hsuan Hsiao, Guillaume Bossis, Henning Urlaub, et al. "Sumoylation inhibits α-synuclein aggregation and toxicity." Journal of Cell Biology 194, no. 1 (July 11, 2011): 49–60. http://dx.doi.org/10.1083/jcb.201010117.

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Posttranslational modification of proteins by attachment of small ubiquitin-related modifier (SUMO) contributes to numerous cellular phenomena. Sumoylation sometimes creates and abolishes binding interfaces, but increasing evidence points to another role for sumoylation in promoting the solubility of aggregation-prone proteins. Using purified α-synuclein, an aggregation-prone protein implicated in Parkinson’s disease that was previously reported to be sumoylated upon overexpression, we compared the aggregation kinetics of unmodified and modified α-synuclein. Whereas unmodified α-synuclein formed fibrils, modified α-synuclein remained soluble. The presence of as little as 10% sumoylated α-synuclein was sufficient to delay aggregation significantly in vitro. We mapped SUMO acceptor sites in α-synuclein and showed that simultaneous mutation of lysines 96 and 102 to arginine significantly impaired α-synuclein sumoylation in vitro and in cells. Importantly, this double mutant showed increased propensity for aggregation and cytotoxicity in a cell-based assay and increased cytotoxicity in dopaminergic neurons of the substantia nigra in vivo. These findings strongly support the model that sumoylation promotes protein solubility and suggest that defects in sumoylation may contribute to aggregation-induced diseases.
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Dissertations / Theses on the topic "Α-synuclein aggregation"

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Oliveira, Márcia Santos. "Modulation of α-synuclein aggregation and toxicity." Master's thesis, Faculdade de Ciências e Tecnologia, 2013. http://hdl.handle.net/10362/11195.

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Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina
It is widely known that α-synuclein (aSyn) is an amyloidogenic protein prone to aggregation. This protein is found in specific inclusions named Lewy bodies in the surviving neurons of Parkinsons’s disease patients and other synucleinopathy brains. This aggregation process is greatly affected by different post-translational modifications, such as phosphorylation, acetylation, and glycation. Lately it was shown that aSyn oligomeric species are more toxic than the inclusion bodies. Heat shock proteins (HSPs) are molecular chaperones able to modulate the folding and refolding of proteins. Its overexpression in Parkinson’s disease models reduces and prevents aSyn aggregation. As the reduction of aSyn aggregation can lead to an eventual accumulation of oligomeric species which may cause cell damage, the main goal of this work is to better understand the role of HSPs in aSyn oligomer formation, clarifying which are the aSyn resulting species formed in the presence of HSPs. Moreover, as glycation is suggested to accelerate abnormal protein deposition, we aimed to investigate how HSPs interfere with the oligomerization process of glycated aSyn. In this study Hsp70 seemed to induce recombinant aSyn oligomerization, generating higher molecular weight species with no associated toxicity. On the other hand, Hsp27 reduced aSyn oligomerization in vitro possibly by inducing the formation of non-reactive small oligomers. MGO glycation increased protein aggregation and cell death. Interestingly, Hsp27 overexpression reversed glycated aSyn aggregation and its associated toxicity. These results demonstrate the importance of HSPs modulation as a possible target of Parkinson’s disease therapeutics.
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Waudby, Christopher Andrew. "Structural and biophysical studies of α-synuclein and protein aggregation." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611252.

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Piroska, Marian-Leonard. "Engineering artificial biomolecular condensates to study the aggregation of α-Synuclein." Electronic Thesis or Diss., Sorbonne université, 2023. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2023SORUS542.pdf.

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Les maladies neurodégénératives, telles que les maladies d'Alzheimer, de Parkinson et de Huntington, sont des maladies incurables caractérisées par une perte progressive de neurones, entraînant des déficits cognitifs et moteurs chez les patients. Le développement de traitements efficaces est actuellement limité par notre compréhension incomplète des mécanismes à l’origine de l’initiation et de la progression de la maladie. Une caractéristique dominante observée dans les tissus affectés par les ces maladies est la présence de protéines agrégées, qui sont devenues la marque de maladies telles que la maladie de Parkinson et la maladie d’Alzheimer. Ainsi, le processus d’agrégation jouerait un rôle central dans la pathogenèse de la maladie. Cependant, les mécanismes spécifiques qui sous-tendent la transition des protéines solubles vers leur état agrégé restent insaisissables. Des recherches récentes ont proposé la séparation de phase (PS) comme étape intermédiaire critique dans la formation d'agrégats de protéines. La PS est un phénomène physique dans lequel certaines protéines subissent une transition de phase, formant des gouttelettes distinctes ayant des propriétés de liquide dans l'environnement cellulaire. Les condensats biomoléculaires sont impliqués dans divers processus physiologiques, mais sont de plus en plus supposes d’être sujets à des comportements aberrants pouvant déclencher des conditions pathologiques. Bien que prometteuse, l’étude du rôle du PS dans le contexte des maladies neurodégénératives reste une tâche difficile en raison de la composition complexe des condensats cellulaires. Ils sont constitués de dizaines, voire de centaines de biomolécules différentes, notamment des protéines, des acides nucléiques et des lipides, créant un milieu complexe qui exige des approches de recherche innovantes. Pour améliorer l'étude de la PS dans le contexte des maladies neurodégénératives, nous avons développé une méthode de formation et de dissolution contrôlées de condensats biomoléculaires enrichis en protéines impliquées dans l'agrégation pathologique. Tout d’abord, nous avons créé des condensats contenant de l’α-synucléine (α-Syn), le principal facteur pathologique de la maladie de Parkinson et d’autres pathologies. L'α-Syn est connue comme une protéine de type prion, ce qui signifie que son agrégat se propage de cellule en cellule et modèle l'agrégation de l'α-Syn cytosolique soluble, favorisant ainsi la progression de la maladie. Cependant, on sait peu de choses sur ce phénomène en ce qui concerne l’état condensé de la protéine. Pour simuler cela, nous avons exposé des cellules exprimant nos condensats α-Syn à des agrégats α-Syn préformés sous forme fibrillaire. Nous avons observé que les fibrilles déclenchaient la transition des condensats de leur état liquide à une forme agrégée ayant des propriétés solides et présentant des marqueurs biochimiques caractéristiques des amyloïdes. Cela nous a permis de proposer un modèle dans lequel la phase condensée de α-Syn accélère la propagation des agrégats pathologiques, en fournissant un pool de protéines concentrées pouvant subir plus facilement une transition amyloïde via le mécanisme de type prion. Par la suite, nous avons construit des condensats artificiels enrichis en α-Syn et la synapsine. Dans les neurones, α-Syn et la synapsine interagissent aux extrémités présynaptiques, où ils jouent un rôle important dans la libération des neurotransmetteurs en contrôlant le regroupement, le trafic et la libération de conteneurs de neurotransmetteurs appelés vésicules synaptiques. Nos condensats d'α-Syn/synapsine étaient eux également soumis à une transition liquide-solide médiée par les fibrilles d'α-Syn
Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's disease, are incurable illnesses characterized by the progressive degeneration of neurons, leading to cognitive and motor deficits in affected individuals. The development of effective treatments is currently limited by our incomplete understanding of the underlying mechanisms that drive disease initiation and progression. One prevailing characteristic observed in the tissues affected by neurodegenerative diseases is the presence of aggregated proteins, which have become hallmarks of diseases such as Parkinson’s and Alzheimer’s. Thus, the aggregation process is believed to play a pivotal role in disease pathogenesis. However, the specific mechanisms underlying the transition of soluble proteins to their aggregated state remain elusive. Recent research has proposed phase separation (PS) as a critical intermediate step in the formation of protein aggregates. PS is a physical phenomenon wherein certain proteins undergo a phase transition, forming distinct liquid-like droplets within the cellular environment. Biomolecular condensates are involved in various physiological cellular processes, but are also increasingly believed to be subject to aberrant behaviours that can trigger pathological conditions. Although promising, studying the role of PS in the context of neurodegenerative diseases is a challenging task, due to the intricate composition of cellular condensates. They consist of tens to hundreds of different biomolecules, including proteins, nucleic acids, and lipids, creating a complex milieu that demands innovative research approaches. To improve the study of LLPS in the context of neurodegenerative diseases, we have developed a method for the controlled formation and dissolution of biomolecular condensates enriched in proteins involved in pathological aggregation. First, we created condensates containing α-synuclein (α-Syn), the main pathological factor in Parkinson’s disease and other pathologies. α-Syn is known as a prion-like protein, meaning that its aggregates spreads from cell to cell and template the aggregation of soluble cytosolic α-Syn, promoting the progression of the disease. However, little is known about this phenomenon with respect to the condensed state of the protein. To simulate this phenomenon, we exposed cells expressing our α-Syn condensates to preformed α-Syn aggregates in fibrillar form. We observed that fibrils triggered the transition of condensates from their liquid-like state to an aggregated form with solid-like properties and exhibiting biochemical markers characteristic of amyloids. This allowed us to propose a model where the condensed phase of α-Syn speeds up the propagation of pathological aggregates, by providing a pool of concentrated protein that can undergo more easily an amyloid transition via the prion-like pathway. Subsequently, we have built artificial condensates enriched in α-Syn together with synapsin. In neurons, α-Syn and synapsin interact at the presynaptic termini, where they play an important role in the release of neurotransmitters by controlling the clustering, trafficking and release of membrane-enclosed neurotransmitter containers called synaptic vesicles. In our setting α-Syn/synapsin condensates were also subject to a liquid-to-solid transition mediated by α-Syn fibrils
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Rcom-H'cheo-Gauthier, Alexandre Nay. "The Protective Effect of Calbindin-D28K on a-Synuclein Aggregation in α- Synucleinopathies." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/368168.

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Neurodegeneration in Dementia with Lewy Bodies (DLB) and Parkinson’s disease (PD) is associated with the formation of neuronal inclusion bodies composed mainly of aggregated α-synuclein (α-syn) protein. Aggregation may be associated with disturbed Ca2+ homeostasis and oxidative stress. Post-mortem studies have shown relative sparing of neurons in PD that are positive for the Ca2+ buffering protein, Calbindin-D28k (CB). CB has been shown to be induced by the hormonal form of vitamin D, Calcitriol, and could be induced by other vitamin D analogue such as Calcipotriol (Cp). Furthermore, recent cell culture and in vitro studies have shown that α-syn aggregation can be induced by potassium depolarization, hence we hypothesized that Cp may suppress their formation. We investigated the interplay between α-syn aggregation, expression of the calbindin-D28k (CB) Ca2+-buffering protein and oxidative stress in neurons by comparing DLB and “healthy” human brain tissue and examining a unilateral oxidative stress lesion model of -syn disease (rotenone mouse), using the combination of immunofluorescence double labelling and Western blot (WB) analysis. DLB cases showed a greater proportion of CB-positive (CB+) neurons in affected brain regions compared to normal cases. Lewy bodies were present predominantly in CB-negative (CB-) neurons and were virtually undetected in CB+ neurons.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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Peduzzo, Alessia [Verfasser]. "Mechanistic insights into α-synuclein aggregation: from fibril stability to surface nucleation / Alessia Peduzzo." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2019. http://d-nb.info/1201881978/34.

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Rivers, Robert Clay. "Biophysical analysis of the aggregation behaviour and structural properties of α- and β-synuclein." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612821.

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Cheruvara, Harish. "Intracellular peptide library screening to derive inhibitors of Parkinson's disease associated α-synuclein aggregation." Thesis, University of Essex, 2015. http://repository.essex.ac.uk/16040/.

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Aggregation of α-synuclein (α-syn) into toxic fibrils is a pathogenic hallmark of Parkinson’s disease (PD). This research aimed to develop peptides capable of inhibiting α-syn aggregation using a semi-rational design combined with a multiplexed intracellular Protein-fragment Complementation Assay (PCA) library screening system. Successfully selected peptides must bind to full length α-syn and lower its toxicity to confer bacterial growth. PCA selected peptides were characterized using several biophysical assays and a cell viability assay. The peptides were screened using library templates based on α-syn71-82 initially and later on the α-syn45-54 region in which many key mutations associated with early onset PD are found. In both cases we targeted the peptide libraries at the wild type protein or again by using mutated versions of α-syn. Results demonstrate that some of those selected peptides had the effect of delaying or even preventing the aggregation process, with others providing more subtle effects in reversing the fully formed amyloid fibrils. PCA peptides selected against 71-82 region of wild type α-syn showed a moderate level of efficacy whereas against mutants, it showed a low level of efficacy in inhibiting amyloid fibril formation. In the final part of the study, the peptide selected against 45-54 region of wild type α-syn was capable of preventing the aggregation and reducing the amyloid cytotoxicity at an equimolar ratio. We have thus demonstrated that the PCA strategy can be used as a generalised method for deriving peptide antagonists of α-syn aggregation, together with a new region; α-syn45-54 as an inhibitor target and produced a peptide inhibitor expected to provide a scaffold for future drug candidates to slow or even prevent the onset of PD.
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Fillon, Gwenaëlle. "Pathologies associated to α-synuclein aggregation in primary culture models of multiple system atrophy." Paris 6, 2006. http://www.theses.fr/2006PA066030.

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Roman, Andrei. "Tau protein aggregation and α-synuclein dysfunction : development of new in vitro and in vivo models to study neurodegenerative diseases." Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0281.

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Les signatures histopathologiques de principales maladies neurodégénératives - maladie d'Alzheimer et la maladie de Parkinson - sont les enchevêtrements neurofibrillaires formés par la protéine tau et les corps de Lewy, formés par l'α-synucleine agrégée. Les mécanismes précis du repliement et de l'agrégation de ces protéines, pour la protéine tau comme pour l'α-synucleine, ne sont pas totalement compris à ce jour. Ici, nous nous sommes intéressés à cette question en utilisant des modèles in vitro et in vivo. En étudiant l'agrégation tau in vitro, nous avons mis en évidence un nouvel auto- assemblage réversible de tau, qui dépend de la température et de la présence d’ions zinc, et qui est a priori différent de l'agrégation de tau en présence d'inducteurs d'agrégation tels que l'héparine. Ce processus pourrait néanmoins être impliqué dans les premières étapes de l'agrégation pathologique de tau. Dans une deuxième partie nous avons développé des modèles murin pour étudier les dysfonctionnement de l’α-synucleine. Nous avons montré que l’α-synucleine est directement impliquée dans le développement embryonnaire de régions spécifiques du système nerveux, et qu'elle a des propriétés modulatrices seulement sur les neurones dopaminergiques de la substantia nigra, qui sont touchés dans la maladie de Parkinson.Les résultats obtenus dans nos études de deux protéines qui subissent une agrégation pathogène et forment des inclusions intracellulaires ont contribué à la compréhension des processus moléculaires et cellulaires associés à la dégénérescence neuronale, ce qui fournira de nouvelles pistes pour développer de nouvelles stratégies de thérapies de maladies neurodégénératives
The histopathological hallmarks of the most common neurodegenerative diseases – Alzheimer’s disease and Parkinson’s disease are neurofibrillary tangles formed by tau protein and Lewy bodies inclusions formed by aggregated α-synuclein. The formation and accumulation of these proteins into inclusions cause functional disruptions of the cytoskeleton and leads to neuronal degeneration. The precise mechanisms of tau and synuclein misfolding and aggregation leading to those cellulare incluses, even though very studied, are not fully understood neither for tau protein nor for α-synuclein.Here we have addressed this question using both in vitro and in vivo models. Investigating tau aggregation in vitro, we have found a reversible self-assembly of tau, which depends on temperature and is induced by zinc ions, which is different from the tau aggregation in the presence of aggregation-inducers such as heparin. This process could be implicated in the first steps of tau pathological aggregation. In a second part, we have developed a mouse model for studying the α-synuclein dysfunction. We have shown that α- synuclein is directly involved in the embryonic development of the specific regions of the nervous system, and that it has modulating effect only on the populations of dopaminergic neurons of substantia nigra, which are affected in Parkinson’s disease.Results obtained in our studies of two proteins that undergo pathogenic aggregation and form intracellular inclusions contributed to understanding of molecular and cellular processes associated with neuronal degeneration, which is important for the development of new disease-modifying therapies of neurodegenerative disorders
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APRILE, FRANCESCO ANTONIO. "Extrinsic factors affecting amyloid aggregation." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/27834.

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Abstract:
Protein conformational diseases (PCD) include a range of degenerative disorders in which specific peptides or proteins misfold and aberrantly self-assemble, eventually forming amyloid-like fibrils, which constitute the hallmark of many neurodegenerative diseases. Plenty of works demonstrated that amyloid aggregation is strongly influenced by several extrinsic factors, such as high concentrations of macromolecules or the presence of proteases and chaperons. Molecular chaperones have been recognised as key players in the avoidance of amyloid fibril formation and, in particular, recent evidences demonstrate that low levels of chaperone heat-shock protein 70 kDa (Hsp70) are strictly related to the formation of intra-neuronal inclusions associated with Parkinson‘s (PD) and polyglutamine (polyQ) diseases. Human Hsp70 is composed of two major functional domains connected by a conserved interdomain linker: the 44-kDa N-terminal nucleotide-binding domain (NBD), with ATPase activity, followed by the 30-kDa substrate-binding domain (SBD) that contains a C-terminal lid subdomain (LS). Using a battery of Hsp70 variants, including full-length Hsp70 and SBD truncated variants, we have been able to discover an interaction between the LS of SBD and the interdomain linker, which we propose could play an important role in the allosteric communication between NBD and SBD. Therefore, we analyzed the anti-amyloidogenic activity of Hsp70, using two model proteins: alpha-synuclein (AS), whose deposition in the brain is associated with PD and the polyQ protein ataxin-3 (AT3), the causative agent of the Machado-Joseph disease (MCD). We demonstrated Hsp70 is able to interact and stabilize pre-fibrillar species formed during amyloid aggregation and that the binding mechanism of these species is different from that of the monomeric protein. Plenty of evidence supports the idea that protein aggregation observed in in vitro experimental conditions is different from that naturally occurring in in vivo systems. This is also related with the fact that the high concentration of macromolecules present in the intra- and extra-cellular compartments, a condition known as molecular crowding (MC), strongly affects protein folding and aggregation. Here, we successfully employed Escherichia coli as in vivo model for studying the aggregation mechanism of the polyQ protein ataxin-3 (AT3) in the presence of MC. In particular we investigated the relationship between the aggregation pathway and cytotoxicity and we were able to characterize the kinetic of formation of aggregated toxic and non-toxic species of AT3. Our future efforts will be aimed to investigate in vivo Hsp70 action by analyzing structural and physiological features of AT3 aggregated species formed in the intracellular environment of E. coli that co-express Hsp70 under different conditions.
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Books on the topic "Α-synuclein aggregation"

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Rongve, Arvid, and Dag Aarsland. Dementia with Lewy bodies and Parkinson’s disease dementia. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199644957.003.0035.

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Dementia with Lewy bodies and Parkinson’s disease dementia belong to the α-synucleinopathies, a family of diseases pathologically characterized by aggregation of α-synuclein in Lewy bodies in the brain. In this chapter we present the epidemiological data for both conditions including new data on MCI. Clinical diagnostic criteria are reviewed and the different neuropathology staging systems for DLB and PDD and the most important genetic findings are considered. Biomarkers in DLB and PDD with particular focus on imaging techniques like CIT-SPECT and MRI are described. Important clinical symptoms in both conditions are presented in detail and the most important clinical differential diagnoses are discussed. Pharmacological and non- pharmacological treatment of different symptoms in both conditions are discussed with particular emphasis on the choline esterase inhibitors and antipsychotic medications.New data on memantine are presented.
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Book chapters on the topic "Α-synuclein aggregation"

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Paleologou, Katerina E., and Omar M. A. El-Agnaf. "α-Synuclein Aggregation and Modulating Factors." In Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease, 109–64. Dordrecht: Springer Netherlands, 2012. http://dx.doi.org/10.1007/978-94-007-5416-4_6.

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Moosa, Mahdi Muhammad, Josephine C. Ferreon, and Allan Chris M. Ferreon. "Single-Molecule FRET Detection of Early-Stage Conformations in α-Synuclein Aggregation." In Methods in Molecular Biology, 221–33. New York, NY: Springer New York, 2019. http://dx.doi.org/10.1007/978-1-4939-9124-2_17.

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Gromiha, M. Michael, S. Biswal, A. M. Thangakani, S. Kumar, G. J. Masilamoni, and D. Velmurugan. "Role of Protein Aggregation and Interactions between α-Synuclein and Calbindin in Parkinson’s Disease." In Intelligent Computing Theories and Technology, 677–84. Berlin, Heidelberg: Springer Berlin Heidelberg, 2013. http://dx.doi.org/10.1007/978-3-642-39482-9_78.

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Bentea, Lucian, Peter Csaba Ölveczky, and Eduard Bentea. "Using Probabilistic Strategies to Formalize and Compare α-Synuclein Aggregation and Propagation under Different Scenarios." In Computational Methods in Systems Biology, 92–105. Berlin, Heidelberg: Springer Berlin Heidelberg, 2013. http://dx.doi.org/10.1007/978-3-642-40708-6_8.

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Kumar Chatterjee, Swapan, Snigdha Saha, and Shahin Muhammed T.K. "COVID-19 and Its Impact on Onset and Progression of Parkinson’s and Cognitive Dysfunction." In COVID-19 Pandemic, Mental Health and Neuroscience - New Scenarios for Understanding and Treatment [Working Title]. IntechOpen, 2023. http://dx.doi.org/10.5772/intechopen.105667.

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In the COVID-19 pandemic, neurological complications have emerged as a significant cause of morbidity and mortality. A wide range of neurological manifestations ranging from cognitive or memory disturbances, headache, loss of smell or taste, confusion, and disabling strokes have been reported during and post COVID conditions. The COVID-19 virus can utilize two possible pathways for invasion into the brain, either through retrograde axonal transport (olfactory route) or by crossing the blood-brain barrier (BBB). Furthermore, the production of SARS-CoV-2-associated cytokines, such as interleukin (IL)-6, IL-17, IL-1b, and tumor necrosis factor (TNF), is able to disrupt the BBB. The neuroinvasive nature of SARS-CoV-2 has a more severe impact on patients with preexisting neurological manifestations such as Parkinson’s disease (PD). Pathological features of PD include selective loss of dopaminergic neurons in the substantia nigra pars compacta and aggregation of α-syn proteins present in neurons. Interaction between SARS-COV-2 infection and α-synuclein might have long-term implications on the onset of Parkinsonism by the formation of toxic protein clumps called amyloid fibrils—a hallmark of Parkinson’s. Molecular modeling is an emerging tool to predict potential inhibitors against the enzyme α-synuclein in neurodegenerative diseases by using plant bioactive molecules.
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Polverino de Laureto, Patrizia, Luana Palazzi, and Laura Acquasaliente. "Polyphenols as Potential Therapeutic Drugs in Neurodegeneration." In Neuroprotection - New Approaches and Prospects. IntechOpen, 2020. http://dx.doi.org/10.5772/intechopen.89575.

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Several therapeutic approaches have been suggested so far for the treatment of neurodegenerative diseases, but to date, there are no approved therapies. The available ones are only symptomatic; they are employed to mitigate the disease manifestations and to improve the patient life quality. These diseases are characterized by the accumulation and aggregation of misfolded proteins in the nervous system, with different specific hallmarks. The onset mechanisms are not completely elucidated. Some promising approaches are focused on the inhibition of the amyloid aggregation of the proteins involved in the etiopathology of the disease, such as Aβ peptide, Tau, and α-synuclein, or on the increase of their clearance in order to avoid their aberrant accumulation. Here, we summarize traditional and new therapeutic approaches proposed for Alzheimer’s and Parkinson’s diseases and the recent technologies for brain delivery.
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El-Mansoury, Bilal, Omar El Hiba, Mustapha Agnaou, Arumugam Radhakrishan Jayakumar, Abdelaati El Khiat, Kholoud Kahim, Samira Boulbaroud, et al. "Neuropathology of Parkinson's Disease." In Experimental and Clinical Evidence of the Neuropathology of Parkinson’s Disease, 82–101. IGI Global, 2023. http://dx.doi.org/10.4018/978-1-6684-5156-4.ch006.

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Parkinson's disease (PD) is a progressive neurodegenerative movement disorder of great concern of which no proven neuroprotective or neurorestorative therapies are available. It is characterized mainly by the degeneration of dopamine (DA) producing neurons in the substantia nigra (SN) pars compacta (SNpc) resulting in nigrostriatal pathway dysregulation and eventually disturbed subcortico-cortical interactions. The pathophysiological mechanisms leading to PD development are not completely understood. Several mechanisms and pathway dysfunctions have been proposed as they play a critical role in the pathogenesis of PD. These include oxidative stress, dysfunctional mitochondria, neuroinflammation, ubiquitin proteasomal dysfunction, and α-synuclein protein aggregation. This chapter will provide an overview on neuropathology, pathogenesis, and the recent pathophysiological mechanisms involved in PD.
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Bala, Sapna, Anamika Misra, Upinder Kaur, and Sankha Shubhra Chakrabarti. "Resveratrol: A Novel Drug for the Management of Neurodegenerative Disorders." In Traditional Medicine for Neuronal Health, 230–51. BENTHAM SCIENCE PUBLISHERS, 2023. http://dx.doi.org/10.2174/9789815040197123010015.

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Resveratrol is a naturally occurring polyphenol (stilbenoid) that works as a phytoalexin, a part of plants’ defense system against infection, ultraviolet radiation, stress and injury. Common dietary sources of resveratrol include grapes, berries, peanuts, red wine, and some herbal preparations. In animal models, resveratrol exhibits a wide spectrum of potential therapeutic activities, including antioxidant, anti-inflammatory, neuroprotective, and longevity-promoting properties. Resveratrol mimics the antioxidant, anti-aging, and neuroprotective effects of caloric restriction, mainly mediated through the increased expression of genes encoding antioxidants and the anti-aging factors (AMPK and Sirtuin 1). Therapeutic strategies for the treatment of neurodegenerative diseases currently have several shortcomings. Naturally occurring compounds may play a significant role in augmenting these therapeutic options. Resveratrol has been shown to maintain homeostasis, protect the brain against oxidative stress, preserve neuronal function, and ultimately minimize age-related neurological decline. It has shown positive effects in animal models and cell culture-based experiments in treating Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, Huntington’s disease, and other neurodegenerative diseases. Resveratrol enhances learning memory and neurogenesis and alleviates neural apoptosis in the hippocampus of AD mice. Beneficial effects of resveratrol in PD result from the inhibition of α-synuclein aggregation and cytotoxicity, lowering of total and oligomeric α-synuclein levels, reduction of neuroinflammation, and oxidative stress. Clinical trials are also evaluating the role of the drug in the major neurodegenerative disorders.
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Bell, Rosie, Michele Vendruscolo, and Janet R. Kumita. "Probing the effects of N-terminal acetylation on α-synuclein structure, aggregation and cytotoxicity." In Methods in Enzymology. Elsevier, 2023. http://dx.doi.org/10.1016/bs.mie.2022.09.003.

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Javed, Hayate, and Shreesh Ojha. "Therapeutic Potential of Baicalein in Parkinson’s Disease: Focus on Inhibition of α-Synuclein Oligomerization and Aggregation." In Synucleins - Biochemistry and Role in Diseases. IntechOpen, 2020. http://dx.doi.org/10.5772/intechopen.83589.

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Conference papers on the topic "Α-synuclein aggregation"

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Dietrich, Heidelinde R. C., Richard L. van den Doel, Wolfgang Hoyer, Wim van Oel, Guus Liqui Lung, Yuval Garini, Thomas Jovin, and Ian T. Young. "Adaptation of nanoarrays for the study of α-synuclein aggregation: preliminary results." In Biomedical Optics 2005, edited by Dan V. Nicolau, Joerg Enderlein, Robert C. Leif, Daniel L. Farkas, and Ramesh Raghavachari. SPIE, 2005. http://dx.doi.org/10.1117/12.587493.

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