Journal articles: '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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Taguchi, Yumiko V., Erica L. Gorenberg, Maria Nagy, Drake Thrasher, Wayne A. Fenton, Laura Volpicelli-Daley, Arthur L. Horwich, and Sreeganga S. Chandra. "Hsp110 mitigates α-synuclein pathology in vivo." Proceedings of the National Academy of Sciences 116, no. 48 (November 4, 2019): 24310–16. http://dx.doi.org/10.1073/pnas.1903268116.

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Parkinson’s disease is characterized by the aggregation of the presynaptic protein α-synuclein and its deposition into pathologic Lewy bodies. While extensive research has been carried out on mediators of α-synuclein aggregation, molecular facilitators of α-synuclein disaggregation are still generally unknown. We investigated the role of molecular chaperones in both preventing and disaggregating α-synuclein oligomers and fibrils, with a focus on the mammalian disaggregase complex. Here, we show that overexpression of the chaperone Hsp110 is sufficient to reduce α-synuclein aggregation in a mammalian cell culture model. Additionally, we demonstrate that Hsp110 effectively mitigates α-synuclein pathology in vivo through the characterization of transgenic Hsp110 and double-transgenic α-synuclein/Hsp110 mouse models. Unbiased analysis of the synaptic proteome of these mice revealed that overexpression of Hsp110 can override the protein changes driven by the α-synuclein transgene. Furthermore, overexpression of Hsp110 is sufficient to prevent endogenous α-synuclein templating and spread following injection of aggregated α-synuclein seeds into brain, supporting a role for Hsp110 in the prevention and/or disaggregation of α-synuclein pathology.

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Chia, Sean, Patrick Flagmeier, Johnny Habchi, Veronica Lattanzi, Sara Linse, Christopher M. Dobson, Tuomas P. J. Knowles, and Michele Vendruscolo. "Monomeric and fibrillar α-synuclein exert opposite effects on the catalytic cycle that promotes the proliferation of Aβ42 aggregates." Proceedings of the National Academy of Sciences 114, no. 30 (July 11, 2017): 8005–10. http://dx.doi.org/10.1073/pnas.1700239114.

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The coaggregation of the amyloid-β peptide (Aβ) and α-synuclein is commonly observed in a range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. The complex interplay between Aβ and α-synuclein has led to seemingly contradictory results on whether α-synuclein promotes or inhibits Aβ aggregation. Here, we show how these conflicts can be rationalized and resolved by demonstrating that different structural forms of α-synuclein exert different effects on Aβ aggregation. Our results demonstrate that whereas monomeric α-synuclein blocks the autocatalytic proliferation of Aβ42 (the 42-residue form of Aβ) fibrils, fibrillar α-synuclein catalyses the heterogeneous nucleation of Aβ42 aggregates. It is thus the specific balance between the concentrations of monomeric and fibrillar α-synuclein that determines the outcome of the Aβ42 aggregation reaction.

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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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Shan, Frank Y., Kar-Ming Fung, Tarek Zieneldien, Janice Kim, Chuanhai Cao, and Jason H. Huang. "Examining the Toxicity of α-Synuclein in Neurodegenerative Disorders." Life 11, no. 11 (October 22, 2021): 1126. http://dx.doi.org/10.3390/life11111126.

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α-synuclein is considered the main pathological protein in a variety of neurodegenerative disorders, such as Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. As of now, numerous studies have been aimed at examining the post-translational modifications of α-synuclein to determine their effects on α-synuclein aggregation, propagation, and oligomerization, as well as the potential cellular pathway dysfunctions caused by α-synuclein, to determine the role of the protein in disease progression. Furthermore, α-synuclein also appears to contribute to the fibrilization of tau and amyloid beta, which are crucial proteins in Alzheimer’s disease, advocating for α-synuclein’s preeminent role in neurodegeneration. Due to this, investigating the mechanisms of toxicity of α-synuclein in neurodegeneration may lead to a more proficient understanding of the timeline progression in neurodegenerative synucleinopathies and could thereby lead to the development of potent targeted therapies.

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Vajhøj, Charlotte, Benjamin Schmid, Ania Alik, Ronald Melki, Karina Fog, Bjørn Holst, and Tina Charlotte Stummann. "Establishment of a human induced pluripotent stem cell neuronal model for identification of modulators of A53T α-synuclein levels and aggregation." PLOS ONE 16, no. 12 (December 21, 2021): e0261536. http://dx.doi.org/10.1371/journal.pone.0261536.

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Inhibiting formation or promoting degradation of α-synuclein aggregates are among the therapeutical approaches under investigation as disease-modifying treatment strategies for Parkinson’s disease. To support these developments, several in vitro models based on seeded α-synuclein aggregation have been established in immortalized cell lines and murine primary neurons. Here, we report on a humanized model with a reproducibility and throughput that enables its use in supporting target identification and validation in pharmacological research. A human induced pluripotent stem cell (iPSC) line was genetically modified to express HA-tagged α-synuclein with the point mutation in position 53 from Alanine to Threonine (A53T) under an inducible system and differentiated into cortical neurons expressing neuronal markers and exhibiting spontaneous activity. Intracellular α-synuclein aggregation was triggered by exposure to exogenous added fibrillated recombinant wild-type human α-synuclein fibrils91 and demonstrated by several endpoints; the formation of Triton-insoluble SDS-soluble α-synuclein, biochemically in a fluorescence resonance energy transfer based aggregation assay and by immunocytochemistry of phosphorylated α-synuclein positive puncta. We demonstrate the feasibility of upscaling the iPSC neuron production for drug discovery and that the model has a suitable dynamic range allowing for both detection of increased and decreased α-synuclein aggregation. Moreover, gene modulation is feasible using siRNAs, making the model suitable for genetic screening for modulators of α-synuclein aggregation. Data on effects of USP8, USP13 and USP9X knockdown on α-synuclein expression and aggregation contradicts published data from immortalized cell lines and murine systems. This highlight the importance of including humanized neuronal models in the confirmation of biological mechanisms in specific variations of Parkinson’s disease.

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Koopman, Herjan, Simon Jackson, Oleg Anichtchik, and Camille Carroll. "LPS INDUCES AGGREGATION OF α-SYNUCLEIN IN MONOCYTES." Journal of Neurology, Neurosurgery & Psychiatry 86, no. 11 (October 14, 2015): e4.188-e4. http://dx.doi.org/10.1136/jnnp-2015-312379.93.

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It is well recognised that Parkinson's disease (PD) is associated with gastrointestinal problems appearing before onset of motor symptoms. An important role for the enteric nervous system (ENS) has been suggested. We hypothesize that inflammatory responses are involved in the onset and progression of PD, with a pivotal role for monocytes/macrophages in the gut. We show that lipopolysaccharide (LPS) can induce the expression and aggregation of monomeric α-synuclein in a human monocyte cell line (MM6). 24 Hours stimulation with LPS resulted in 3-6.5-fold increase in monomeric α-synuclein (determined by Western blotting), whilst tetrameric α-synuclein increased 1.3-2.2-fold. Preliminary results suggest that trimeric α-synuclein is secreted extracellularly after stimulation with LPS. Specificity of the observed bands was confirmed by pre-absorbing the antibody with recombinant α-synuclein. These findings were supported by immunocytochemistry: double immunofluorescence showed co-localization of aggregated α-synuclein with an antibody recognizing only oligomeric α-synuclein, confirming the presence of aggregates. These results suggest a role for inflammatory responses leading to increased monomeric and aggregated α-synuclein levels in monocytes. Secreted α-synuclein oligomers could mimic ‘prion-like’ spreading of aggregates to neurons, as observed in interneuronal transfer. The combination of aggregated α-synuclein with inflammatory mediators could influence the ENS, affecting onset and progression of PD.

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Ikeda, Aya, Kenya Nishioka, Hongrui Meng, Masashi Takanashi, Iwao Hasegawa, Tsuyoshi Inoshita, Kahori Shiba-Fukushima, et al. "Mutations in CHCHD2 cause α-synuclein aggregation." Human Molecular Genetics 28, no. 23 (October 10, 2019): 3895–911. http://dx.doi.org/10.1093/hmg/ddz241.

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Abstract Mutations in CHCHD2 are linked to a familial, autosomal dominant form of Parkinson’s disease (PD). The gene product may regulate mitochondrial respiratory function. However, whether mitochondrial dysfunction induced by CHCHD2 mutations further yields α-synuclein pathology is unclear. Here, we provide compelling genetic evidence that mitochondrial dysfunction induced by PD-linked CHCHD2 T61I mutation promotes α-synuclein aggregation using brain autopsy, induced pluripotent stem cells (iPSCs) and Drosophila genetics. An autopsy of an individual with CHCHD2 T61I revealed widespread Lewy pathology with both amyloid plaques and neurofibrillary tangles that appeared in the brain stem, limbic regions and neocortex. A prominent accumulation of sarkosyl-insoluble α-synuclein aggregates, the extent of which was comparable to that of a case with α-synuclein (SNCA) duplication, was observed in CHCHD2 T61I brain tissue. The prion-like activity and morphology of α-synuclein fibrils from the CHCHD2 T61I brain tissue were similar to those of fibrils from SNCA duplication and sporadic PD brain tissues. α-Synuclein insolubilization was reproduced in dopaminergic neuron cultures from CHCHD2 T61I iPSCs and Drosophila lacking the CHCHD2 ortholog or expressing the human CHCHD2 T61I. Moreover, the combination of ectopic α-synuclein expression and CHCHD2 null or T61I enhanced the toxicity in Drosophila dopaminergic neurons, altering the proteolysis pathways. Furthermore, CHCHD2 T61I lost its mitochondrial localization by α-synuclein in Drosophila. The mislocalization of CHCHD2 T61I was also observed in the patient brain. Our study suggests that CHCHD2 is a significant mitochondrial factor that determines α-synuclein stability in the etiology of PD.

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Guo, Min, Jian Wang, Yanxin Zhao, Yiwei Feng, Sida Han, Qiang Dong, Mei Cui, and Kim Tieu. "Microglial exosomes facilitate α-synuclein transmission in Parkinson’s disease." Brain 143, no. 5 (May 1, 2020): 1476–97. http://dx.doi.org/10.1093/brain/awaa090.

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Abstract Accumulation of neuronal α-synuclein is a prominent feature in Parkinson’s disease. More recently, such abnormal protein aggregation has been reported to spread from cell to cell and exosomes are considered as important mediators. The focus of such research, however, has been primarily in neurons. Given the increasing recognition of the importance of non-cell autonomous-mediated neurotoxicity, it is critical to investigate the contribution of glia to α-synuclein aggregation and spread. Microglia are the primary phagocytes in the brain and have been well-documented as inducers of neuroinflammation. How and to what extent microglia and their exosomes impact α-synuclein pathology has not been well delineated. We report here that when treated with human α-synuclein preformed fibrils, exosomes containing α-synuclein released by microglia are fully capable of inducing protein aggregation in the recipient neurons. Additionally, when combined with microglial proinflammatory cytokines, these exosomes further increased protein aggregation in neurons. Inhibition of exosome synthesis in microglia reduced α-synuclein transmission. The in vivo significance of these exosomes was demonstrated by stereotaxic injection of exosomes isolated from α-synuclein preformed fibrils treated microglia into the mouse striatum. Phosphorylated α-synuclein was observed in multiple brain regions consistent with their neuronal connectivity. These animals also exhibited neurodegeneration in the nigrostriatal pathway in a time-dependent manner. Depleting microglia in vivo dramatically suppressed the transmission of α-synuclein after stereotaxic injection of preformed fibrils. Mechanistically, we report here that α-synuclein preformed fibrils impaired autophagy flux by upregulating PELI1, which in turn, resulted in degradation of LAMP2 in activated microglia. More importantly, by purifying microglia/macrophage derived exosomes in the CSF of Parkinson’s disease patients, we confirmed the presence of α-synuclein oligomer in CD11b+ exosomes, which were able to induce α-synuclein aggregation in neurons, further supporting the translational aspect of this study. Taken together, our study supports the view that microglial exosomes contribute to the progression of α-synuclein pathology and therefore, they may serve as a promising therapeutic target for Parkinson’s disease.

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Gaspar, Ricardo, Georg Meisl, Alexander K. Buell, Laurence Young, Clemens F. Kaminski, Tuomas P. J. Knowles, Emma Sparr, and Sara Linse. "Acceleration of α-synuclein aggregation." Amyloid 24, sup1 (March 16, 2017): 20–21. http://dx.doi.org/10.1080/13506129.2017.1292904.

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Giehm, Lise, Nikolai Lorenzen, and Daniel E. Otzen. "Assays for α-synuclein aggregation." Methods 53, no. 3 (March 2011): 295–305. http://dx.doi.org/10.1016/j.ymeth.2010.12.008.

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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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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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Murvai, Nikoletta, Gabriella Gellen, András Micsonai, Gitta Schlosser, and József Kardos. "Cross-Linked α-Synuclein as Inhibitor of Amyloid Formation." International Journal of Molecular Sciences 24, no. 17 (August 29, 2023): 13403. http://dx.doi.org/10.3390/ijms241713403.

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The aggregation and amyloid formation of α-synuclein is associated with Parkinson’s disease and other synucleinopathies. In its native, monomeric form α-synuclein is an intrinsically disordered protein represented by highly dynamic conformational ensembles. Inhibition of α-synuclein aggregation using small molecules, peptides, or proteins has been at the center of interest in recent years. Our aim was to explore the effects of cross-linking on the structure and aggregation/amyloid formation properties of α-synuclein. Comparative analysis of available high-resolution amyloid structures and representative structural models and MD trajectory of monomeric α-synuclein revealed that potential cross-links in the monomeric protein are mostly incompatible with the amyloid forms and thus might inhibit fibrillation. Monomeric α-synuclein has been intramolecularly chemically cross-linked under various conditions using different cross-linkers. We determined the location of cross-links and their frequency using mass spectrometry and found that most of them cannot be realized in the amyloid structures. The inhibitory potential of cross-linked proteins has been experimentally investigated using various methods, including thioflavin-T fluorescence and transmission electron microscopy. We found that conformational constraints applied by cross-linking fully blocked α-synuclein amyloid formation. Moreover, DTSSP-cross-linked molecules exhibited an inhibitory effect on the aggregation of unmodified α-synuclein as well.

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Wen, Tianzhi, Jian Chen, Wenqian Zhang, and Jiyan Pang. "Design, Synthesis and Biological Evaluation of α-Synuclein Proteolysis-Targeting Chimeras." Molecules 28, no. 11 (May 31, 2023): 4458. http://dx.doi.org/10.3390/molecules28114458.

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α-Synuclein aggregation under pathological conditions is one of the causes of related neurodegenerative diseases. PROTACs (proteolysis targeting chimeras) are bifunctional small molecules that induce a post-translational erasure of proteins via the ubiquitination of target proteins by E3 ubiquitin ligase and subsequent proteasomal degradation. However, few research studies have been conducted for targeted protein degradation of α-synuclein aggregates. In this article, we have designed and synthesized a series of small-molecule degraders 1–9 based on a known α-synuclein aggregation inhibitor sery384. In silico docking studies of sery384 with α-synuclein aggregates were accomplished to ensure that the compounds bound to α-synuclein aggregates specifically. The protein level of α-synuclein aggregates was determined to evaluate the degradation efficiency of PROTAC molecules on α-synuclein aggregates in vitro. The results show that compound 5 had the most significant degradation effect, with DC50 of 5.049 μM, and could induce the degradation of α-synuclein aggregates in a time- and dose-dependent manner in vitro. Furthermore, compound 5 could inhibit the elevation of the ROS level caused by overexpression and aggregation of α-synuclein and protect H293T cells from α-synuclein toxicity. Conclusively, our results provide a new class of small-molecule degraders and an experimental basis for the treatment of α-synuclein related neurodegenerative diseases.

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Levine, Paul M., Ana Galesic, Aaron T. Balana, Anne-Laure Mahul-Mellier, Mariana X. Navarro, Cesar A. De Leon, Hilal A. Lashuel, and Matthew R. Pratt. "α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease." Proceedings of the National Academy of Sciences 116, no. 5 (January 16, 2019): 1511–19. http://dx.doi.org/10.1073/pnas.1808845116.

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A compelling link is emerging between the posttranslational modification O-GlcNAc and protein aggregation. A prime example is α-synuclein, which forms toxic aggregates that are associated with neurodegeneration in Parkinson’s and related diseases. α-Synuclein has been shown to be O-GlcNAcylated at nine different positions in in vivo proteomics experiments from mouse and human tissues. This raises the possibility that O-GlcNAc may alter the aggregation of this protein and could be both an important biological mediator of neurodegeneration and also a therapeutic target. Here, we expand upon our previous research in this area through the chemical synthesis of six site-specifically O-GlcNAcylated variants of α-synuclein. We then use a variety of biochemical experiments to show that O-GlcNAc in general inhibits the aggregation of α-synuclein but can also alter the structure of α-synuclein aggregates in site-specific ways. Additionally, an α-synuclein protein bearing three O-GlcNAc modifications can inhibit the aggregation of unmodified protein. Primary cell culture experiments also show that several of the O-GlcNAc sites inhibit the toxicity of extracellular α-synuclein fibers that are likely culprits in the spread of Parkinson’s disease. We also demonstrate that O-GlcNAcylation can inhibit the aggregation of an aggressive mutant of α-synuclein, indicating that therapies currently in development that increase this modification might be applied in animal models that rely on this mutant. Finally, we also show that the pan-selective antibody for O-GlcNAc does not generally recognize this modification on α-synuclein, potentially explaining why it remains understudied. These results support further development of O-GlcNAcylation tools and therapeutic strategies in neurodegenerative diseases.

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Won, Seok Joon, Rebecca Fong, Nicholas Butler, Jennifer Sanchez, Yiguan Zhang, Candance Wong, Olive Tambou Nzoutchoum, Annie Huynh, June Pan, and Raymond A. Swanson. "Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo." Antioxidants 11, no. 12 (December 15, 2022): 2466. http://dx.doi.org/10.3390/antiox11122466.

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Both genetic and environmental factors increase risk for Parkinson’s disease. Many of the known genetic factors influence α-synuclein aggregation or degradation, whereas most of the identified environmental factors produce oxidative stress. Studies using in vitro approaches have identified mechanisms by which oxidative stress can accelerate the formation of α-synuclein aggregates, but there is a paucity of evidence supporting the importance of these processes over extended time periods in brain. To assess this issue, we evaluated α-synuclein aggregates in brains of three transgenic mouse strains: hSyn mice, which overexpress human α-synuclein in neurons and spontaneously develop α-synuclein aggregates; EAAT3−/− mice, which exhibit a neuron-specific impairment in cysteine uptake and resultant neuron-selective chronic oxidative stress; and double-transgenic hSyn/EAAT3−/− mice. Aggregate formation was evaluated by quantitative immunohistochemistry for phosphoserine 129 α-synuclein and by an α-synuclein proximity ligation assay. Both methods showed that the double transgenic hSyn/EAAT3−/− mice exhibited a significantly higher α-synuclein aggregate density than littermate hSyn mice in each brain region examined. Negligible aggregate formation was observed in the EAAT3−/− mouse strain, suggesting a synergistic rather than additive interaction between the two genotypes. A similar pattern of results was observed in assessments of motor function: the pole test and rotarod test. Together, these observations indicate that chronic, low-grade neuronal oxidative stress promotes α-synuclein aggregate formation in vivo. This process may contribute to the mechanism by which environmentally induced oxidative stress contributes to α-synuclein pathology in idiopathic Parkinson’s disease.

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Pujols, Jordi, Samuel Peña-Díaz, Diana F. Lázaro, Francesca Peccati, Francisca Pinheiro, Danilo González, Anita Carija, et al. "Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons." Proceedings of the National Academy of Sciences 115, no. 41 (September 24, 2018): 10481–86. http://dx.doi.org/10.1073/pnas.1804198115.

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Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D–treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein–induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson’s disease.

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Morgan, Sophie A., Isabelle Lavenir, Juan Fan, Masami Masuda-Suzukake, Daniela Passarella, Michael A. DeTure, Dennis W. Dickson, Bernardino Ghetti, and Michel Goedert. "α-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species." Journal of Biological Chemistry 295, no. 19 (March 24, 2020): 6652–64. http://dx.doi.org/10.1074/jbc.ra119.012179.

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Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies.

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Hartlage-Rübsamen, Maike, Alexandra Bluhm, Sandra Moceri, Lisa Machner, Janett Köppen, Mathias Schenk, Isabel Hilbrich, et al. "A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies." Acta Neuropathologica 142, no. 3 (July 26, 2021): 399–421. http://dx.doi.org/10.1007/s00401-021-02349-5.

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AbstractParkinson’s disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may—in analogy to pGlu-Aβ peptides in Alzheimer’s disease—act as a seed for pathogenic protein aggregation.

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Perni, Michele, Céline Galvagnion, Alexander Maltsev, Georg Meisl, Martin B. D. Müller, Pavan K. Challa, Julius B. Kirkegaard, et al. "A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity." Proceedings of the National Academy of Sciences 114, no. 6 (January 17, 2017): E1009—E1017. http://dx.doi.org/10.1073/pnas.1610586114.

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The self-assembly of α-synuclein is closely associated with Parkinson’s disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic reduction of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson’s disease and related conditions.

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El-Agnaf, Omar M. A., and G. Brent Irvine. "Aggregation and properties of α‒synuclein and related proteins." Spectroscopy 15, no. 3,4 (2001): 141–50. http://dx.doi.org/10.1155/2001/939274.

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α-Synuclein has been identified as a component of intracellular fibrillar protein deposits in several neurodegenerative diseases, and two mutant forms have been associated with early onset Parkinson's disease. A fragment of α-synuclein has also been identified as the non-Aβ component of Alzheimer's disease amyloid (NAC). Ageing solutions of α-synuclein and NAC leads to formation of β-sheet, detectable by circular dichroism spectroscopy, and aggregation to form amyloid-like fibrils, detectable by electron microscopy. Differences in the rates of aggregation of the fibrils formed by α-synuclein and the two mutant proteins are presented. The toxicity of α-synuclein and related peptides towards neurons is also discussing in relation to the aetiology of neurodegenerative diseases.Experiments on fragments of NAC have enabled the region of NAC responsible for its aggregation and toxicity to be identified.

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Palazzi, Luana, Benedetta Fongaro, Manuela Leri, Laura Acquasaliente, Massimo Stefani, Monica Bucciantini, and Patrizia Polverino de Laureto. "Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC." International Journal of Molecular Sciences 22, no. 11 (June 2, 2021): 6008. http://dx.doi.org/10.3390/ijms22116008.

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The interplay between α-synuclein and dopamine derivatives is associated with oxidative stress-dependent neurodegeneration in Parkinson’s disease (PD). The formation in the dopaminergic neurons of intraneuronal inclusions containing aggregates of α-synuclein is a typical hallmark of PD. Even though the biochemical events underlying the aberrant aggregation of α-synuclein are not completely understood, strong evidence correlates this process with the levels of dopamine metabolites. In vitro, 3,4-dihydroxyphenylacetaldehyde (DOPAL) and the other two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET), share the property to inhibit the growth of mature amyloid fibrils of α-synuclein. Although this effect occurs with the formation of differently toxic products, the molecular basis of this inhibition is still unclear. Here, we provide information on the effect of DOPAC on the aggregation properties of α-synuclein and its ability to interact with membranes. DOPAC inhibits α-synuclein aggregation, stabilizing monomer and inducing the formation of dimers and trimers. DOPAC-induced oligomers did not undergo conformational transition in the presence of membranes, and penetrated the cell, where they triggered autophagic processes. Cellular assays showed that DOPAC reduced cytotoxicity and ROS production induced by α-synuclein aggregates. Our findings show that the early radicals resulting from DOPAC autoxidation produced covalent modifications of the protein, which were not by themselves a primary cause of either fibrillation or membrane binding inhibition. These findings are discussed in the light of the potential mechanism of DOPAC protection against the toxicity of α-synuclein aggregates to better understand protein and catecholamine biology and to eventually suggest a scaffold that can help in the design of candidate molecules able to interfere in α-synuclein aggregation.

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Hlushchuk, Irena, Justyna Barut, Mikko Airavaara, Kelvin Luk, Andrii Domanskyi, and Piotr Chmielarz. "Cell Culture Media, Unlike the Presence of Insulin, Affect α-Synuclein Aggregation in Dopaminergic Neurons." Biomolecules 12, no. 4 (April 9, 2022): 563. http://dx.doi.org/10.3390/biom12040563.

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There are several links between insulin resistance and neurodegenerative disorders such as Parkinson’s disease. However, the direct influence of insulin signaling on abnormal α-synuclein accumulation—a hallmark of Parkinson’s disease—remains poorly explored. To our best knowledge, this work is the first attempt to investigate the direct effects of insulin signaling on pathological α-synuclein accumulation induced by the addition of α-synuclein preformed fibrils in primary dopaminergic neurons. We found that modifying insulin signaling through (1) insulin receptor inhibitor GSK1904529A, (2) SHIP2 inhibitor AS1949490 or (3) PTEN inhibitor VO-OHpic failed to significantly affect α-synuclein aggregation in dopaminergic neurons, in contrast to the aggregation-reducing effects observed after the addition of glial cell line-derived neurotrophic factor. Subsequently, we tested different media formulations, with and without insulin. Again, removal of insulin from cell culturing media showed no effect on α-synuclein accumulation. We observed, however, a reduced α-synuclein aggregation in neurons cultured in neurobasal medium with a B27 supplement, regardless of the presence of insulin, in contrast to DMEM/F12 medium with an N2 supplement. The effects of culture conditions were present only in dopaminergic but not in primary cortical or hippocampal cells, indicating the unique sensitivity of the former. Altogether, our data contravene the direct involvement of insulin signaling in the modulation of α-synuclein aggregation in dopamine neurons. Moreover, we show that the choice of culturing media can significantly affect preformed fibril-induced α-synuclein phosphorylation in a primary dopaminergic cell culture.

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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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Bluhm, Alexandra, Sarah Schrempel, Stephan von von Hörsten, Anja Schulze, and Steffen Roßner. "Proteolytic α-Synuclein Cleavage in Health and Disease." International Journal of Molecular Sciences 22, no. 11 (May 21, 2021): 5450. http://dx.doi.org/10.3390/ijms22115450.

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In Parkinson’s disease, aggregates of α-synuclein within Lewy bodies and Lewy neurites represent neuropathological hallmarks. However, the cellular and molecular mechanisms triggering oligomeric and fibrillary α-synuclein aggregation are not fully understood. Recent evidence indicates that oxidative stress induced by metal ions and post-translational modifications such as phosphorylation, ubiquitination, nitration, glycation, and SUMOylation affect α-synuclein conformation along with its aggregation propensity and neurotoxic profiles. In addition, proteolytic cleavage of α-synuclein by specific proteases results in the formation of a broad spectrum of fragments with consecutively altered and not fully understood physiological and/or pathological properties. In the present review, we summarize the current knowledge on proteolytical α-synuclein cleavage by neurosin, calpain-1, cathepsin D, and matrix metalloproteinase-3 in health and disease. We also shed light on the contribution of the same enzymes to proteolytical processing of pathogenic proteins in Alzheimer’s disease and report potential cross-disease mechanisms of pathogenic protein aggregation.

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Antonschmidt, Leif, Rıza Dervişoğlu, Vrinda Sant, Kumar Tekwani Movellan, Ingo Mey, Dietmar Riedel, Claudia Steinem, Stefan Becker, Loren B. Andreas, and Christian Griesinger. "Insights into the molecular mechanism of amyloid filament formation: Segmental folding of α-synuclein on lipid membranes." Science Advances 7, no. 20 (May 2021): eabg2174. http://dx.doi.org/10.1126/sciadv.abg2174.

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Recent advances in the structural biology of disease-relevant α-synuclein fibrils have revealed a variety of structures, yet little is known about the process of fibril aggregate formation. Characterization of intermediate species that form during aggregation is crucial; however, this has proven very challenging because of their transient nature, heterogeneity, and low population. Here, we investigate the aggregation of α-synuclein bound to negatively charged phospholipid small unilamellar vesicles. Through a combination of kinetic and structural studies, we identify key time points in the aggregation process that enable targeted isolation of prefibrillar and early fibrillar intermediates. By using solid-state nuclear magnetic resonance, we show the gradual buildup of structural features in an α-synuclein fibril filament, revealing a segmental folding process. We identify distinct membrane-binding domains in α-synuclein aggregates, and the combined data are used to present a comprehensive mechanism of the folding of α-synuclein on lipid membranes.

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Ma, Qiu-Lan, Piu Chan, Mitsunobu Yoshii, and Kenji Uéda. "α-Synuclein aggregation and neurodegenerative diseases." Journal of Alzheimer's Disease 5, no. 2 (April 22, 2003): 139–48. http://dx.doi.org/10.3233/jad-2003-5208.

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Crunkhorn, Sarah. "Rescuing α-synuclein aggregation in PD." Nature Reviews Drug Discovery 21, no. 1 (December 2, 2021): 20. http://dx.doi.org/10.1038/d41573-021-00201-9.

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Lundvig, Ditte, Evo Lindersson, and Poul Henning Jensen. "Pathogenic effects of α-synuclein aggregation." Molecular Brain Research 134, no. 1 (March 2005): 3–17. http://dx.doi.org/10.1016/j.molbrainres.2004.09.001.

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Ghosh, Dhiman, Surabhi Mehra, Shruti Sahay, Pradeep K. Singh, and Samir K. Maji. "α-synuclein aggregation and its modulation." International Journal of Biological Macromolecules 100 (July 2017): 37–54. http://dx.doi.org/10.1016/j.ijbiomac.2016.10.021.

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Afitska, Kseniia, Anna Fucikova, Volodymyr V. Shvadchak, and Dmytro A. Yushchenko. "α-Synuclein aggregation at low concentrations." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1867, no. 7-8 (July 2019): 701–9. http://dx.doi.org/10.1016/j.bbapap.2019.05.003.

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Pandey, Neeraj, Jeffrey Strider, William C. Nolan, Sherry X. Yan, and James E. Galvin. "Curcumin inhibits aggregation of α-synuclein." Acta Neuropathologica 115, no. 4 (January 10, 2008): 479–89. http://dx.doi.org/10.1007/s00401-007-0332-4.

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Takano, Mariko, Erika Tashiro, Akira Kitamura, Hiroshi Maita, Sanae M. M. Iguchi-Ariga, Masataka Kinjo, and Hiroyoshi Ariga. "Prefoldin prevents aggregation of α-synuclein." Brain Research 1542 (January 2014): 186–94. http://dx.doi.org/10.1016/j.brainres.2013.10.034.

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Gao, Huiling, Hehong Sun, Nan Yan, Pu Zhao, He Xu, Wei Zheng, Xiaoyu Zhang, Tao Wang, Chuang Guo, and Manli Zhong. "ATP13A2 Declines Zinc-Induced Accumulation of α-Synuclein in a Parkinson’s Disease Model." International Journal of Molecular Sciences 23, no. 14 (July 21, 2022): 8035. http://dx.doi.org/10.3390/ijms23148035.

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Parkinson’s disease (PD) is characterized by the presence of Lewy bodies caused by α-synuclein. The imbalance of zinc homeostasis is a major cause of PD, promoting α-synuclein accumulation. ATP13A2, a transporter found in acidic vesicles, plays an important role in Zn2+ homeostasis and is highly expressed in Lewy bodies in PD-surviving neurons. ATP13A2 is involved in the transport of zinc ions in lysosomes and exosomes and inhibits the aggregation of α-synuclein. However, the potential mechanism underlying the regulation of zinc homeostasis and α-synuclein accumulation by ATP13A2 remains unexplored. We used α-synuclein-GFP transgenic mice and HEK293 α-synuclein-DsRed cell line as models. The spatial exploration behavior of mice was significantly reduced, and phosphorylation levels of α-synuclein increased upon high Zn2+ treatment. High Zn2+ also inhibited the autophagy pathway by reducing LAMP2a levels and changing the expression of LC3 and P62, by reducing mitochondrial membrane potential and increasing the expression of cytochrom C, and by activating the ERK/P38 apoptosis signaling pathway, ultimately leading to increased caspase 3 levels. These protein changes were reversed after ATP13A2 overexpression, whereas ATP13A2 knockout exacerbated α-synuclein phosphorylation levels. These results suggest that ATP13A2 may have a protective effect on Zn2+-induced abnormal aggregation of α-synuclein, lysosomal dysfunction, and apoptosis.

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Ventura, Salvador, and Francisca Pinheiro. "Inducing α-synuclein compaction: a new strategy for inhibiting α-synuclein aggregation?" Neural Regeneration Research 14, no. 11 (2019): 1897. http://dx.doi.org/10.4103/1673-5374.259608.

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Scheibe, Christian, Christiaan Karreman, Stefan Schildknecht, Marcel Leist, and Karin Hauser. "Synuclein Family Members Prevent Membrane Damage by Counteracting α-Synuclein Aggregation." Biomolecules 11, no. 8 (July 21, 2021): 1067. http://dx.doi.org/10.3390/biom11081067.

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The 140 amino acid protein α-synuclein (αS) is an intrinsically disordered protein (IDP) with various roles and locations in healthy neurons that plays a key role in Parkinson’s disease (PD). Contact with biomembranes can lead to α-helical conformations, but can also act as s seeding event for aggregation and a predominant β-sheet conformation. In PD patients, αS is found to aggregate in various fibrillary structures, and the shift in aggregation and localization is associated with disease progression. Besides full-length αS, several related polypeptides are present in neurons. The role of many αS-related proteins in the aggregation of αS itself is not fully understood Two of these potential aggregation modifiers are the αS splicing variant αS Δexon3 (Δ3) and the paralog β-synuclein (βS). Here, polarized ATR-FTIR spectroscopy was used to study the membrane interaction of these proteins individually and in various combinations. The method allowed a continuous monitoring of both the lipid structure of biomimetic membranes and the aggregation state of αS and related proteins. The use of polarized light also revealed the orientation of secondary structure elements. While αS led to a destruction of the lipid membrane upon membrane-catalyzed aggregation, βS and Δ3 aggregated significantly less, and they did not harm the membrane. Moreover, the latter proteins reduced the membrane damage triggered by αS. There were no major differences in the membrane interaction for the different synuclein variants. In combination, these observations suggest that the formation of particular protein aggregates is the major driving force for αS-driven membrane damage. The misbalance of αS, βS, and Δ3 might therefore play a crucial role in neurodegenerative disease.

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Chen, Chiung Mei, Chih-Hsin Lin, Yih-Ru Wu, Chien-Yu Yen, Yu-Ting Huang, Jia-Lan Lin, Chung-Yin Lin, et al. "Lactulose and Melibiose Inhibit α-Synuclein Aggregation and Up-Regulate Autophagy to Reduce Neuronal Vulnerability." Cells 9, no. 5 (May 16, 2020): 1230. http://dx.doi.org/10.3390/cells9051230.

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Parkinson’s disease (PD) is a neurodegenerative disease characterized by selective dopaminergic (DAergic) neuronal degeneration in the substantia nigra (SN) and proteinaceous α-synuclein-positive Lewy bodies and Lewy neuritis. As a chemical chaperone to promote protein stability and an autophagy inducer to clear aggregate-prone proteins, a disaccharide trehalose has been reported to alleviate neurodegeneration in PD cells and mouse models. Its trehalase-indigestible analogs, lactulose and melibiose, also demonstrated potentials to reduce abnormal protein aggregation in spinocerebellar ataxia cell models. In this study, we showed the potential of lactulose and melibiose to inhibit α-synuclein aggregation using biochemical thioflavin T fluorescence, cryogenic transmission electron microscopy (cryo-TEM) and prokaryotic split Venus complementation assays. Lactulose and melibiose further reduced α-synuclein aggregation and associated oxidative stress, as well as protected cells against α-synuclein-induced neurotoxicity by up-regulating autophagy and nuclear factor, erythroid 2 like 2 (NRF2) pathway in DAergic neurons derived from SH-SY5Y cells over-expressing α-synuclein. Our findings strongly indicate the potential of lactulose and melibiose for mitigating PD neurodegeneration, offering new drug candidates for PD treatment.

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Zhou, Wenbo, Chunmei Long, Anthony Fink, and Vladimir Uversky. "Calbindin-D28K acts as a calcium-dependent chaperone suppressing α-synuclein fibrillation in vitro." Open Life Sciences 5, no. 1 (February 1, 2010): 11–20. http://dx.doi.org/10.2478/s11535-009-0071-8.

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Abstractα-Synuclein, a natively unfolded protein aggregation which is implicated in the pathogenesis of Parkinson’s disease and several other neurodegenerative diseases, is known to interact with a great number of unrelated proteins. Some of these proteins, such as β-synuclein and DJ-1, were shown to inhibit α-synuclein aggregation in vitro and in vivo therefore acting as chaperones. Since calbindin-D28K is co-localized with Ca2+ neuronal membrane pumps, and since α-synuclein is also found in the membrane proximity, these two proteins can potentially interact in vivo. Here we show that calbindin-D28K interacts with α-synuclein and inhibits its fibrillation in a calcium-dependent manner, therefore potentially acting as a calcium-dependent chaperone.

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Paleologou, K. E., G. B. Irvine, and O. M. A. El-Agnaf. "α-Synuclein aggregation in neurodegenerative diseases and its inhibition as a potential therapeutic strategy." Biochemical Society Transactions 33, no. 5 (October 26, 2005): 1106–10. http://dx.doi.org/10.1042/bst0331106.

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There is strong evidence for the involvement of α-synuclein in the pathologies of several neurodegenerative disorders, including PD (Parkinson's disease). Development of disease appears to be linked to processes that increase the rate at which α-synuclein forms aggregates. These processes include increased protein concentration (via either increased rate of synthesis or decreased rate of degradation), and altered forms of α-synuclein (such as truncations, missense mutations, or chemical modifications by oxidative reactions). Aggregated forms of the protein are toxic to cells and one therapeutic strategy would be to reduce the rate at which aggregation occurs. To this end we have designed several peptides that reduce α-synuclein aggregation. A cell-permeable version of one such peptide was able to inhibit the DNA damage induced by Fe(II) in neuronal cells transfected with α-synuclein (A53T), a familial PD-associated mutation.

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Ko, Eun Ae, Hyun Jin Min, and Jeon-Soo Shin. "Interaction of High Mobility Group Box-1 (HMGB1) with α-synuclein and its aggregation (172.28)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 172.28. http://dx.doi.org/10.4049/jimmunol.188.supp.172.28.

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Abstract HMGB1, also known as amphoterin, is an abundant non-histone nuclear protein and is involved in neurite outgrowth and neuronal migration in CNS. The accumulation of misfolded proteins and neuronal loss are common features in many neurodegenerative diseases. The aggregation of α-synuclein is implicated as a pathologic hallmark of Parkinson’s disease. In this study, we demonstrated that HMGB1, which was translocated to the cytoplasm by the treatment of lysosomal protease inhibitor of MG-132, was co-localized with α-synuclein in SH-SY5Y neuroblastoma cells. HMGB1 showed much more binding to α-synuclein E46K mutant, which is the site of one of familial mutations that accelerate oligomerization, suggesting that HMGB1 could enhance the aggregation of α-synuclein mutant. The binding of HMGB1 and α-synuclein isolated from brain tissue that is originated from Parkinson’s disease patient is under investigation.

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Journal articles on the topic 'Α-synuclein aggregation'

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