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3. Helical sulfonyl-γ-AApeptides modulating Aβ oligomerization and cytotoxicity by recognizing Aβ helix.

Author

Heng Liu, Yunpeng Cui, Xue Zhao, Lulu Wei, Xudong Wang, Ning Shen, Odom, Timothy, Xuming Li, Lawless, William, Karunarathne, Kanchana, Muschol, Martin, Wayne Guida, Chuanhai Cao, Libin Ye, and Jianfeng Cai

Subjects
CYTOTOXINS, NUCLEAR magnetic resonance spectroscopy, OLIGOMERIZATION, CIRCULAR dichroism, HELICAL structure
Abstract

In contrast to prevalent strategies which make use of β-sheet mimetics to block Aβ fibrillar growth, in this study, we designed a series of sulfonyl-γ-AApeptide helices that targeted the crucial α-helix domain of Aβ13-26 and stabilized Aβ conformation to avoid forming the neurotoxic Aβ oligomeric β-sheets. Biophysical assays such as amyloid kinetics and TEM demonstrated that the Aβ oligomerization and fibrillation could be greatly prevented and even reversed in the presence of sulfonyl-γ-AApeptides in a sequence-specific and dose-dependent manner. The studies based on circular dichroism, Two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) spectra unambiguously suggested that the sulfonyl-γ-AApeptide Ab-6 could bind to the central region of Aβ42 and induce α-helix conformation in Aβ. Additionally, Electrospray ionisation-ion mobility spectrometry–mass spectrometry (ESI-IMS-MS) was employed to rule out a colloidal mechanism of inhibitor and clearly supported the capability of Ab-6 for inhibiting the formation of Aβ aggregated forms. Furthermore, Ab-6 could rescue neuroblastoma cells by eradicating Aβ-mediated cytotoxicity even in the presence of pre-formed Aβ aggregates. The confocal microscopy demonstrated that Ab-6 could still specifically bind Aβ42 and colocalize into mitochondria in the cellular environment, suggesting the rescue of cell viability might be due to the protection of mitochondrial function otherwise impaired by Aβ42 aggregation. Taken together, our studies indicated that sulfonyl-γ-AApeptides as helical peptidomimetics could direct Aβ into the off-pathway helical secondary structure, thereby preventing the formation of Aβ oligomerization, fibrillation and rescuing Aβ induced cell cytotoxicity. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

Author

Blair, Laura J, Nordhues, Bryce A, Hill, Shannon E, Scaglione, K Matthew, O’Leary, John C, Fontaine, Sarah N, Breydo, Leonid, Zhang, Bo, Li, Pengfei, Wang, Li, Cotman, Carl, Paulson, Henry L, Muschol, Martin, Uversky, Vladimir N, Klengel, Torsten, Binder, Elisabeth B, Kayed, Rakez, Golde, Todd E, Berchtold, Nicole, and Dickey, Chad A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Aging, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Acquired Cognitive Impairment, Dementia, Brain Disorders, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid, Animals, CA3 Region, Hippocampal, Case-Control Studies, DNA Methylation, Female, Gene Expression, Gene Expression Regulation, HEK293 Cells, HSP90 Heat-Shock Proteins, Humans, Male, Mice, Mice, Knockout, Middle Aged, Proteasome Endopeptidase Complex, Protein Multimerization, Protein Structure, Quaternary, Proteolysis, Tacrolimus Binding Proteins, Young Adult, tau Proteins, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Aggregation of tau protein in the brain is associated with a class of neurodegenerative diseases known as tauopathies. FK506 binding protein 51 kDa (FKBP51, encoded by FKBP5) forms a mature chaperone complex with Hsp90 that prevents tau degradation. In this study, we have shown that tau levels are reduced throughout the brains of Fkbp5-/- mice. Recombinant FKBP51 and Hsp90 synergized to block tau clearance through the proteasome, resulting in tau oligomerization. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved the species of tau that have been linked to Alzheimer's disease (AD) pathogenesis, blocked amyloid formation, and decreased tangle load in the brain. Alterations in tau turnover and aggregate structure corresponded with enhanced neurotoxicity in mice. In human brains, FKBP51 levels increased relative to age and AD, corresponding with demethylation of the regulatory regions in the FKBP5 gene. We also found that higher FKBP51 levels were associated with AD progression. Our data support a model in which age-associated increases in FKBP51 levels and its interaction with Hsp90 promote neurotoxic tau accumulation. Strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 have the potential to be therapeutically relevant for AD and other tauopathies.

Published
2013

9. Contributors

Author

Aguilar, Marie-Isabel, primary, Andreasen, Maria, additional, Anthony, Neil R., additional, Teran Arce, Fernando, additional, Arnhold, Florian, additional, Arya, Shruti, additional, Attar, Aida, additional, Barbosa, Silvia, additional, Behrens, Manja A., additional, Bekard, Innocent B., additional, Belfort, Georges, additional, Bennink, Martin L., additional, Bereza, Magdalena, additional, Berland, Keith M., additional, Bitan, Gal, additional, Bonn, Mischa, additional, Botelho, Hugo M., additional, Branco dos Santos, Joana, additional, Breydo, Leonid, additional, Cao, Yi, additional, Cappai, Roberto, additional, Cardoso, Isabel, additional, Carrión-Vázquez, Mariano, additional, Carvalho, Sofia B., additional, Carver, John A., additional, Chan, Fiona T.S., additional, Childers, W. Seth, additional, Collins, Jason C., additional, Connelly, Laura, additional, Curtain, Cyril, additional, Dalal, Vijit, additional, De Simone, Alfonso, additional, Donald, Athene M., additional, Dunstan, Dave E., additional, Ecroyd, Heath, additional, Enghild, Jan Johannes, additional, Abelleira, Laura Esther, additional, Fändrich, Marcus, additional, Fernández-Ramírez, María del Carmen, additional, Foderà, Vito, additional, Fritz, Günter, additional, Furukawa, Yoshiaki, additional, Ghodke, Shirin D., additional, Gianni, Stefano, additional, Giese, Armin, additional, Gomes, Cláudio M., additional, Gonçalves, Susana, additional, Greene, Lesley H., additional, Griffin, Michael D.W., additional, Griggs, Amy M., additional, Haass, Christian, additional, Hammarström, Per, additional, Harris, J. Robin, additional, Herrera, Federico, additional, Hervás, Rubén, additional, Hill, Shannon E., additional, Hou, Xu, additional, Howlett, Geoffrey J., additional, Ikezu, Tsuneya, additional, Jang, Hyunbum, additional, Jensen, Grethe V., additional, Kagan, Bruce L., additional, Kaminski, Clemens F., additional, Kawai-Noma, Shigeko, additional, Klechikov, Alexei, additional, Koenderink, Gijsje H., additional, Lal, Ratnesh, additional, Laurents, Douglas V., additional, Le Lan Pham, Chi, additional, LeVine, Harry, additional, Losic, Dusan, additional, Lynn, David G., additional, Malmos, Kirsten G., additional, Martin, Lisandra L., additional, Mechler, Adam I., additional, Mehta, Anil K., additional, Meral, Derya, additional, Milton, Nathaniel G.N., additional, Mok, Yee-Foong, additional, Morozova-Roche, Ludmilla A., additional, Mosquera, Víctor, additional, Mukhopadhyay, Samrat, additional, Mulaj, Mentor, additional, Muschol, Martin, additional, Nielsen, Niels Chr, additional, Nilsson, R., additional, Nübling, Georg, additional, Nussinov, Ruth, additional, Otzen, Daniel E., additional, Outeiro, Tiago Fleming, additional, Pedersen, Jan Skov, additional, Pedersen, Jesper Søndergaard, additional, Peter, K., additional, Pinotsi, Dorothea, additional, Qin, Meng, additional, Ramachandran, Srinivasan, additional, Rekas, Agata, additional, Relini, Annalisa, additional, Rochet, Jean-Christophe, additional, Rothhämel, Sophie, additional, Rudinskiy, Nikita, additional, Sauer, Markus, additional, Kaminski Schierle, Gabriele S., additional, Schleeger, Michael, additional, Schmid, Bettina, additional, Small, David H., additional, Søndergaard, Anne, additional, Sorci, Mirco, additional, Spires-Jones, Tara L., additional, Stenvang, Marcel, additional, Stöckl, Martin, additional, Strecker, Katrin, additional, Subramaniam, Vinod, additional, Svane, Anna S.P., additional, Sweers, Kim K.M., additional, Taboada, Pablo, additional, Taguchi, Hideki, additional, Teoh, Chai Lean, additional, Thorn, David C., additional, Tokuraku, Kiyotaka, additional, Tycko, Robert, additional, Urbanc, Brigita, additional, Uversky, Vladimir N., additional, van den Akker, Corianne C., additional, Vendruscolo, Michele, additional, von Mikecz, Anna, additional, Vukojević, Vladana, additional, Wang, Wei, additional, Weise, Katrin, additional, Winter, Roland, additional, Wu, Jessica W., additional, Xue, Wei-Feng, additional, Yanamandra, Kiran, additional, Ysselstein, Daniel, additional, Žerovnik, Eva, additional, and Zou, Dawei, additional

Published
2014
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11. Origin of metastable oligomers and their effects on amyloid fibril self-assembly† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8sc01479e

Author

Hasecke, Filip, Miti, Tatiana, Perez, Carlos, Barton, Jeremy, Schölzel, Daniel, Gremer, Lothar, Grüning, Clara S. R., Matthews, Garrett, Meisl, Georg, Knowles, Tuomas P. J., Willbold, Dieter, Neudecker, Philipp, Heise, Henrike, Ullah, Ghanim, Hoyer, Wolfgang, and Muschol, Martin

Subjects
Chemistry, macromolecular substances
Abstract

Simultaneous analysis of oligomer and fibril assembly kinetics reveals inhibitory effects of metastable oligomers on amyloid fibril formation., Assembly of rigid amyloid fibrils with their characteristic cross-β sheet structure is a molecular signature of numerous neurodegenerative and non-neuropathic disorders. Frequently large populations of small globular amyloid oligomers (gOs) and curvilinear fibrils (CFs) precede the formation of late-stage rigid fibrils (RFs), and have been implicated in amyloid toxicity. Yet our understanding of the origin of these metastable oligomers, their role as on-pathway precursors or off-pathway competitors, and their effects on the self-assembly of amyloid fibrils remains incomplete. Using two unrelated amyloid proteins, amyloid-β and lysozyme, we find that gO/CF formation, analogous to micelle formation by surfactants, is delineated by a “critical oligomer concentration” (COC). Below this COC, fibril assembly replicates the sigmoidal kinetics of nucleated polymerization. Upon crossing the COC, assembly kinetics becomes biphasic with gO/CF formation responsible for the lag-free initial phase, followed by a second upswing dominated by RF nucleation and growth. RF lag periods below the COC, as expected, decrease as a power law in monomer concentration. Surprisingly, the build-up of gO/CFs above the COC causes a progressive increase in RF lag periods. Our results suggest that metastable gO/CFs are off-pathway from RF formation, confined by a condition-dependent COC that is distinct from RF solubility, underlie a transition from sigmoidal to biphasic assembly kinetics and, most importantly, not only compete with RFs for the shared monomeric growth substrate but actively inhibit their nucleation and growth.

Published
2018

19. Protofibril–Fibril Interactions Inhibit Amyloid Fibril Assembly by Obstructing Secondary Nucleation.

Author

Hasecke, Filip, Niyangoda, Chamani, Borjas, Gustavo, Pan, Jianjun, Matthews, Garrett, Muschol, Martin, and Hoyer, Wolfgang

Subjects
AMYLOID, AMYLOID plaque, NUCLEATION, ATOMIC force microscopy, OLIGOMERS, CHEMICAL kinetics, AMYLOID beta-protein
Abstract

Amyloid‐β peptides (Aβ) assemble into both rigid amyloid fibrils and metastable oligomers termed AβO or protofibrils. In Alzheimer's disease, Aβ fibrils constitute the core of senile plaques, but Aβ protofibrils may represent the main toxic species. Aβ protofibrils accumulate at the exterior of senile plaques, yet the protofibril–fibril interplay is not well understood. Applying chemical kinetics and atomic force microscopy to the assembly of Aβ and lysozyme, protofibrils are observed to bind to the lateral surfaces of amyloid fibrils. When utilizing Aβ variants with different critical oligomer concentrations, the interaction inhibits the autocatalytic proliferation of amyloid fibrils by secondary nucleation on the fibril surface. Thus, metastable oligomers antagonize their replacement by amyloid fibrils both by competing for monomers and blocking secondary nucleation sites. The protofibril—fibril interaction governs their temporal evolution and potential to exert specific toxic activities. [ABSTRACT FROM AUTHOR]

Published
2021
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20. Liquid-Liquid Phase Separation in Supersaturated Lysozyme Solutions and Associated Precipitate Formation/Crystallization

Author

Muschol, Martin and Rosenberger, Franz

Subjects
Solid-State Physics
Abstract

Using cloud point determinations, the phase boundaries (binodals) for metastable liquid-liquid (L-L) separation in supersaturated hen egg white lysozyme solutions with 3%, 5%, and 7% (wlv) NaCl at pH= 4.5 and protein concentrations c between 40 and 400 mg/ml were determined. The critical temperature for the binodal increased approximately linearly with salt concentration. The coexisting liquid phases both remained supersaturated but differed widely in protein concentration. No salt repartitioning was observed between the initial and the two separated liquid phases. After the L-L separation, due to the presence of the high protein concentration phase, crystallization occurred much more rapidly than in the initial solution. At high initial protein concentrations, a metastable gel phase formed at temperatures above the liquid binodal. Both crystal nucleation and gel formation were accelerated in samples that had been cycled through the binodal. Solutions in the gel and L-L regions yielded various types of precipitates. Based on theoretical considerations, previous observations with other proteins, and our experimental results with lysozyme, a generic phase diagram for globular proteins is put forth. A limited region in the (T,c) plane favorable for the growth of protein single crystals is delineated.

Published
1997
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21. Lack of Evidence for Prenucleation Aggregate Formation in Lysozyme Crystal Growth Solutions

Author

Muschol, Martin and Rosenberger, Franz

Subjects
Solid-State Physics
Abstract

There have been numerous claims of large concentrations of prenucleation aggregates in supersaturated as well as undersaturated lysozyme solutions at high salt concentrations. The presence of these aggregates was derived from measurements of the light or neutron scattering intensity, ultracentrifugation and dialysis behavior, as well as over-simplified crystal growth kinetics considerations. In all these interpretations it has been assumed that lysozyme solutions are either ideal or that protein interactions are independent of salt concentration. Contrary to these presumptions, our static and dynamic light scattering experiments provide evidence that lysozyme forms highly non-ideal, strongly interacting solutions. At low salt concentrations, the scattering intensities fall well below the values expected for an ideal, monomeric solution at the same protein concentration, while diffusivities increase with increasing protein concentration. Upon increase in salt concentration, these trends are eventually reversed. This enhancement in scattering intensity and decrease in diffusivity was widely interpreted as sign of aggregate formation. Yet, a quantitative interpretation of the scattering behavior over the whole salt concentration range can only be given in terms of a transition from net repulsion to net attraction between lysozyme monomers. Increased salt screening of the electrostatic repulsion among the protein macro-ions, together with attractive protein interactions, such as van der Waals, hydrophobic and hydration forces, provide an unambiguous mechanism for the observed transition and a more physical interpretation of the various observations.

Published
1996
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22. Interactions in Undersaturated and Supersaturated Lysozyme Solutions: Static and Dynamic Light Scattering Results

Author

Muschol, Martin and Rosenberger, Franz

Subjects
Optics
Abstract

We have performed multiangle static and dynamic light scattering studies of lysozyme solutions at pH=4.7. The Rayleigh ratio R(sub g) and the collective diffusion coefficient D(sub c) were determined as function of both protein concentration c(sub p) and salt concentration c(sub s) with two different salts. At low salt concentrations, the scattering ratio K(sub c)(sub p)/R(sub theta) and diffusivity increased with protein concentration above the values for a monomeric, ideal solution. With increasing salt concentration this trend was eventually reversed. The hydrodynamic interactions of lysozyme in solution, extracted from the combination of static and dynamic scattering data, decreased significantly with increasing salt concentration. These observations reflect changes in protein interactions, in response to increased salt screening, from net repulsion to net attraction. Both salts had the same qualitative effect, but the quantitative behavior did not scale with the ionic strength of the solution. This indicates the presence of salt specific effects. At low protein concentrations, the slopes of K(sub c)(sub p)/R(sub theta) and D(sub c) vs c(sub p) were obtained. The dependence of the slopes on ionic strength was modeled using a DLVO potential for colloidal interactions of two spheres, with the net protein charge Z(sub e) and Hamaker constant A(sub H) as fitting parameters. The model reproduces the observed variations with ionic strength quite well. Independent fits to the static and dynamic data, however, led to different values of the fitting parameters. These and other shortcomings suggest that colloidal interaction models alone are insufficient to explain protein interactions in solutions.

Published
1995
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36. P1–058: The Hsp90 co‐chaperone FKBP51 produces neurotoxic tau oligomers: Implication for aging and Alzheimer's disease

Author

Blair, Laura, primary, Nordhues, Bryce, additional, Hill, Shannon, additional, Scaglione, K. Matthew, additional, O'Leary, John, additional, Breydo, Leonid, additional, Bo, Zhang, additional, Li, Pengfei, additional, Wang, Lily, additional, Cotman, Carl, additional, Paulson, Henry, additional, Muschol, Martin, additional, Uversky, Vladimir, additional, Klengel, Torsten, additional, Binder, Elisabeth, additional, Kayed, Rakez, additional, Berchtold, Nicole, additional, Golde, Todd, additional, and Dickey, Chad, additional

Published
2013
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45. P3-425: Chaperone-mediated modulation of tau aggregation correlates with modifications in tau pathology and synaptic plasticity

Author

Abisambra, Jose F., primary, Blair, Laura J., additional, Jones, Jeffrey R., additional, Kraft, Clara, additional, Hill, Shannon, additional, Rogers, Justin, additional, Koren, John, additional, Jinwal, Umesh K., additional, Lawson, Lisa, additional, Johnson, Amelia G., additional, Jansen-West, Karen, additional, Muschol, Martin, additional, Banko, Jessica, additional, Golde, Todd, additional, Weeber, Edwin J., additional, and Dickey, Chad A., additional

Published
2010
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