共查询到20条相似文献,搜索用时 46 毫秒
1.
Filippo Favretto Jeremy D. Baker Timo Strohker Loren B. Andreas Laura J. Blair Stefan Becker Markus Zweckstetter 《Angewandte Chemie (International ed. in English)》2020,59(14):5643-5646
Peptidylprolyl isomerases (PPIases) catalyze cis/trans isomerization of prolines. The PPIase CypA colocalizes with the Parkinson's disease (PD)‐associated protein α‐synuclein in cells and interacts with α‐synuclein oligomers. Herein, we describe atomic insights into the molecular details of the α‐synuclein/CypA interaction. NMR spectroscopy shows that CypA catalyzes isomerization of proline 128 in the C‐terminal domain of α‐synuclein. Strikingly, we reveal a second CypA‐binding site formed by the hydrophobic sequence 47GVVHGVATVA56, termed PreNAC. The 1.38 Å crystal structure of the CypA/PreNAC complex displays a contact between alanine 53 of α‐synuclein and glutamine 111 in the catalytic pocket of CypA. Mutation of alanine 53 to glutamate, as found in patients with early‐onset PD, weakens the interaction of α‐synuclein with CypA. Our study provides high‐resolution insights into the structure of the PD‐associated protein α‐synuclein in complex with the most abundant cellular cyclophilin. 相似文献
2.
Toxic Dopamine Metabolite DOPAL Forms an Unexpected Dicatechol Pyrrole Adduct with Lysines of α‐Synuclein
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Dr. Jon W. Werner‐Allen Dr. Jenna F. DuMond Dr. Rodney L. Levine Dr. Ad Bax 《Angewandte Chemie (International ed. in English)》2016,55(26):7374-7378
Parkinson's disease has long been known to involve the loss of dopaminergic neurons in the substantia nigra and the coincidental appearance of Lewy bodies containing oligomerized forms of α‐synuclein. The “catecholaldehyde hypothesis” posits a causal link between these two central pathologies mediated by 3,4‐dihydroxyphenylacetaldehyde (DOPAL), the most toxic dopamine metabolite. Here we determine the structure of the dominant product in reactions between DOPAL and α‐synuclein, a dicatechol pyrrole lysine adduct. This novel modification results from the addition of two DOPAL molecules to the Lys sidechain amine through their aldehyde moieties and the formation of a new carbon–carbon bond between their alkyl chains to generate a pyrrole ring. The product is detectable at low concentrations of DOPAL and its discovery should provide a valuable chemical basis for future studies of DOPAL‐induced crosslinking of α‐synuclein. 相似文献
3.
Cyclodextrins 3‐Functionalized with 8‐Hydroxyquinolines: Copper‐Binding Ability and Inhibition of Synuclein Aggregation
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Neurodegenerative diseases such as Parkinson's and Alzheimer's diseases are multifactorial disorders related to protein aggregation, metal dyshomeostasis, and oxidative stress. To advance understanding in this area and to contribute to therapeutic development, many efforts have been directed at devising suitable agents that can target metal ions associated with relevant biomolecules such as α‐synuclein. This paper presents a new cyclodextrin–8‐hydroxyquinoline conjugate and discusses the properties of four cyclodextrins 3‐functionalized with 8‐hydroxyquinoline as copper(II) chelators and inhibitors of copper‐induced synuclein aggregation. The encouraging results establish the potential of cyclodextrin–8‐hydroxyquinoline conjugates as chelators for the control of copper toxicity. 相似文献
4.
Dr. Juan A. Varela Dr. Margarida Rodrigues Dr. Suman De Patrick Flagmeier Dr. Sonia Gandhi Prof. Christopher M. Dobson Prof. David Klenerman Dr. Steven F. Lee 《Angewandte Chemie (International ed. in English)》2018,57(18):4886-4890
Small aggregates of misfolded proteins play a key role in neurodegenerative disorders. Such species have proved difficult to study due to the lack of suitable methods capable of resolving these heterogeneous aggregates, which are smaller than the optical diffraction limit. We demonstrate here an all‐optical fluorescence microscopy method to characterise the structure of individual protein aggregates based on the fluorescence anisotropy of dyes such as thioflavin‐T, and show that this technology is capable of studying oligomers in human biofluids such as cerebrospinal fluid. We first investigated in vitro the structural changes in individual oligomers formed during the aggregation of recombinant α‐synuclein. By studying the diffraction‐limited aggregates we directly evaluated their structural conversion and correlated this with the potential of aggregates to disrupt lipid bilayers. We finally characterised the structural features of aggregates present in cerebrospinal fluid of Parkinson's disease patients and age‐matched healthy controls. 相似文献
5.
Quantum chemical insights into Alzheimer's disease: Curcumin's chelation with Cu(II), Zn(II), and Pd(II) as a mechanism for its prevention
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Krishnan Balasubramanian 《International journal of quantum chemistry》2016,116(14):1107-1119
We provide quantum chemical insights into curcumin's prevention of Alzheimer' disease through curcumin's scavenging of neurotoxic Cu(II), Zn(II), and Pd(II) transition metal ions that catalyze polymerization of amyloid‐β and promote misfolding of amyloid into neurotoxic conformations. We have employed high level quantum chemical computations to study the chelate complexes of curcumin with Cu(II), Zn(II), and Pd(II). Quantum chemically derived structures, IR spectra, and UV‐visible spectra of these complexes corroborate with the observed spectra, confirming that the primary site of chelation is the β‐diketone bridge through the loss of an enolic proton of curcumin. We have also obtained the various structural parameters such as the Mulliken charges on various centers, highest occupied, lowest unoccupied molecular orbitals—all of which confirm that curcumin forms chelate complexes and thus acts as a scavenger of these neurotoxic metal ions preventing Alzheimer's disease. We find that the open‐d‐shell Cu(II) and Pd(II) form nearly square planar complexes while the closed‐d‐shell Zn(II) forms a tetrahedral complex with curcumin. © 2016 Wiley Periodicals, Inc. 相似文献
6.
Valentina Armiento Anna Spanopoulou Aphrodite Kapurniotu 《Angewandte Chemie (International ed. in English)》2020,59(9):3372-3384
Protein misfolding into amyloid fibrils is linked to more than 40 as yet incurable cell‐ and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes. So far, however, only one of the numerous anti‐amyloid molecules has reached patients. This Minireview gives an overview of molecular strategies and peptide chemistry “tools” to design, develop, and discover peptide‐based molecules as anti‐amyloid drug candidates. We focus on two major inhibitor rational design strategies: 1) the oldest and most common strategy, based on molecular recognition elements of amyloid self‐assembly, and 2) a more recent approach, based on cross‐amyloid interactions. We discuss why peptide‐based amyloid inhibitors, in particular their advanced generations, can be promising leads or candidates for anti‐amyloid drugs as well as valuable tools for deciphering amyloid‐mediated cell damage and its link to disease pathogenesis. 相似文献
7.
Atomic‐Resolution Three‐Dimensional Structure of Amyloid β Fibrils Bearing the Osaka Mutation
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Dr. Anne K. Schütz Dr. Toni Vagt Dr. Matthias Huber Dr. Oxana Y. Ovchinnikova Riccardo Cadalbert Dr. Joseph Wall Prof. Dr. Peter Güntert Dr. Anja Böckmann Prof. Dr. Rudi Glockshuber Prof. Dr. Beat H. Meier 《Angewandte Chemie (International ed. in English)》2015,54(1):331-335
Despite its central importance for understanding the molecular basis of Alzheimer's disease (AD), high‐resolution structural information on amyloid β‐peptide (Aβ) fibrils, which are intimately linked with AD, is scarce. We report an atomic‐resolution fibril structure of the Aβ1‐40 peptide with the Osaka mutation (E22Δ), associated with early‐onset AD. The structure, which differs substantially from all previously proposed models, is based on a large number of unambiguous intra‐ and intermolecular solid‐state NMR distance restraints. 相似文献
8.
Dr. Hamed Shaykhalishahi Dr. Aziz Gauhar Michael M. Wördehoff Dr. Clara S. R. Grüning Antonia N. Klein Dr. Oliver Bannach Dr. Matthias Stoldt Prof. Dr. Dieter Willbold Prof. Dr. Torleif Härd Dr. Wolfgang Hoyer 《Angewandte Chemie (International ed. in English)》2015,54(30):8837-8840
Conversion of the intrinsically disordered protein α‐synuclein (α‐syn) into amyloid aggregates is a key process in Parkinson’s disease. The sequence region 35–59 contains β‐strand segments β1 and β2 of α‐syn amyloid fibril models and most disease‐related mutations. β1 and β2 frequently engage in transient interactions in monomeric α‐syn. The consequences of β1–β2 contacts are evaluated by disulfide engineering, biophysical techniques, and cell viability assays. The double‐cysteine mutant α‐synCC, with a disulfide linking β1 and β2, is aggregation‐incompetent and inhibits aggregation and toxicity of wild‐type α‐syn. We show that α‐syn delays the aggregation of amyloid‐β peptide and islet amyloid polypeptide involved in Alzheimer’s disease and type 2 diabetes, an effect enhanced in the α‐synCC mutant. Tertiary interactions in the β1–β2 region of α‐syn interfere with the nucleation of amyloid formation, suggesting promotion of such interactions as a potential therapeutic approach. 相似文献
9.
Yang He Yimin Wang Shu Liu Zifeng Pi Zhiqiang Liu Junpeng Xing Hui Zhou 《Journal of separation science》2020,43(8):1458-1465
As a well‐known traditional Chinese medicine formula, Ding‐Zhi‐Xiao‐Wan has long been used for the routine treatment of Alzheimer's disease. However, the mechanism of Ding‐Zhi‐Xiao‐Wan in treating Alzheimer's disease is unclear. Therefore, a nontargeted metabolomics method based on ultrahigh performance liquid chromatography with quadrupole time‐of‐flight mass spectrometry has been established to explore the metabolic variations in the urine of Alzheimer's disease rats and investigate the therapeutic mechanism of Ding‐Zhi‐Xiao‐Wan on Alzheimer's disease. To develop a better rat model of Alzheimer's disease, amyloid β25‐35 was injected into the bilateral hippocampus of Sprague–Dawley rats. Multivariate analysis approaches were applied to differentiate the urine components between the four groups. Thereafter, a targeted metabolomics method was used to verify the identified endogenous metabolites and determine the mechanism of action of Ding‐Zhi‐Xiao‐Wan. Altogether, 26 potential biomarkers were found, of which 15 biomarkers (10 of which are potential biomarkers found in nontargeted metabolomics) were identified. The results show that Ding‐Zhi‐Xiao‐Wan mainly affects the pathways of taurine and hypotaurine metabolism, tryptophan metabolism, and phenylalanine metabolism. Ding‐Zhi‐Xiao‐Wan might play a role in the treatment of Alzheimer's disease by mediating antioxidative stress, regulation of energy metabolism, improvement of intestinal microbes, and protection of nerve cells. 相似文献
10.
Anionic Oligothiophenes Compete for Binding of X‐34 but not PIB to Recombinant Aβ Amyloid Fibrils and Alzheimer's Disease Brain‐Derived Aβ
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Marcus Bäck Hanna Appelqvist Harry LeVine III K. Peter R. Nilsson 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(51):18335-18338
Deposits comprised of amyloid‐β (Aβ) are one of the pathological hallmarks of Alzheimer's disease (AD) and small hydrophobic ligands targeting these aggregated species are used clinically for the diagnosis of AD. Herein, we observed that anionic oligothiophenes efficiently displaced X‐34, a Congo Red analogue, but not Pittsburgh compound B (PIB) from recombinant Aβ amyloid fibrils and Alzheimer's disease brain‐derived Aβ. Overall, we foresee that the oligothiophene scaffold offers the possibility to develop novel high‐affinity ligands for Aβ pathology only found in human AD brain, targeting a different site than PIB. 相似文献
11.
Isaak Beyer Dr. Nasrollah Rezaei‐Ghaleh Dr. Hans‐Wolfgang Klafki Dr. Olaf Jahn Dr. Ute Haußmann Prof. Dr. Jens Wiltfang Prof. Dr. Markus Zweckstetter Prof. Dr. Hans‐Joachim Knölker 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(25):8685-8693
In addition to the prototypic amyloid‐β (Aβ) peptides Aβ1–40 and Aβ1–42, several Aβ variants differing in their amino and carboxy termini have been described. Synthetic availability of an Aβ variant is often the key to study its role under physiological or pathological conditions. Herein, we report a protocol for the efficient solid‐phase peptide synthesis of the N‐terminally elongated Aβ‐peptides Aβ?3–38, Aβ?3–40, and Aβ?3–42. Biophysical characterization by NMR spectroscopy, CD spectroscopy, an aggregation assay, and electron microscopy revealed that all three peptides were prone to aggregation into amyloid fibrils. Immunoprecipitation, followed by mass spectrometry, indicated that Aβ?3–38 and Aβ?3–40 are generated by transfected cells even in the presence of a tripartite β‐site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. The elongated Aβ peptides starting at Val(?3) can be separated from N‐terminally‐truncated Aβ forms by high‐resolution isoelectric‐focusing techniques, despite virtually identical isoelectric points. The synthetic Aβ variants and the methods presented here are providing tools to advance our understanding of the potential roles of N‐terminally elongated Aβ variants in Alzheimer's disease. 相似文献
12.
Dr. Ewa A. Mirecka Hamed Shaykhalishahi Aziz Gauhar Şerife Akgül Dr. Justin Lecher Prof. Dr. Dieter Willbold Dr. Matthias Stoldt Dr. Wolfgang Hoyer 《Angewandte Chemie (International ed. in English)》2014,53(16):4227-4230
The misfolding and aggregation of the protein α‐synuclein (α‐syn), which results in the formation of amyloid fibrils, is involved in the pathogenesis of Parkinson’s disease and other synucleinopathies. The emergence of amyloid toxicity is associated with the formation of partially folded aggregation intermediates. Here, we engineered a class of binding proteins termed β‐wrapins (β‐wrap proteins) with affinity for α‐synuclein (α‐syn). The NMR structure of an α‐syn:β‐wrapin complex reveals a β‐hairpin of α‐syn comprising the sequence region α‐syn(37–54). The β‐wrapin inhibits α‐syn aggregation and toxicity at substoichiometric concentrations, demonstrating that it interferes with the nucleation of aggregation. 相似文献
13.
Self‐Assembled Cyclic d,l‐α‐Peptides as Generic Conformational Inhibitors of the α‐Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies
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Dr. Marina Chemerovski‐Glikman Eva Rozentur‐Shkop Dr. Michal Richman Dr. Asaf Grupi Asaf Getler Prof. Haim Y. Cohen Dr. Hadassa Shaked Cecilia Wallin Dr. Sebastian K. T. S. Wärmländer Prof. Elisha Haas Prof. Astrid Gräslund Prof. Jordan H. Chill Prof. Shai Rahimipour 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(40):14236-14246
Many peptides and proteins with large sequences and structural differences self‐assemble into disease‐causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross‐interaction. Here, we demonstrate how the self‐assembled, cyclic d,l ‐α‐peptide CP‐2 , which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson′s disease associated α‐synuclein (α‐syn) aggregation to toxic oligomers by an ?off‐pathway“ mechanism. We show that CP‐2 interacts with the N‐terminal and the non‐amyloid‐β component region of α‐syn, which are responsible for α‐syn′s membrane intercalation and self‐assembly, thus changing the overall conformation of α‐syn. CP‐2 also remodels α‐syn fibrils to nontoxic amorphous species and permeates cells through endosomes/lysosomes to reduce the accumulation and toxicity of intracellular α‐syn in neuronal cells overexpressing α‐syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases. 相似文献
14.
Ralf Baumeister Stefan Eimer 《Angewandte Chemie (International ed. in English)》1998,37(21):2978-2982
The cooperative action of three proteases is required to process the APP protein (695–770 amino acids) into small β-amyloid peptides (Aβ, 40–42 amino acids). Aβ aggregates are found in the senile plaques of patients with Alzheimer's disease and play a major role in the onset of this disorder. The functional analysis of several factors that contribute to the production and aggregation of Aβ has enhanced our knowledge of the mechanism of amyloid formation and increased the potential for effective therapeutic treatment. 相似文献
15.
Extracellular deposition of amyloid‐beta (Aβ) protein, a fragment of membrane glycoprotein called β‐amyloid precursor transmembrane protein (βAPP), is the major characteristic for the Alzheimer's disease (AD). However, the structural and mechanistic information of forming Aβ protein aggregates in a lag phase in cell exterior has been still limited. Here, we have performed multiple all‐atom molecular dynamics simulations for physiological 42‐residue amyloid‐beta protein (Aβ42) in explicit water to characterize most plausible aggregation‐prone structure (APS) for the monomer and the very early conformational transitions for Aβ42 protein misfolding process in a lag phase. Monitoring the early sequential conformational transitions of Aβ42 misfolding in water, the APS for Aβ42 monomer is characterized by the observed correlation between the nonlocal backbone H‐bond formation and the hydrophobic side‐chain exposure. Characteristics on the nature of the APS of Aβ42 allow us to provide new insight into the higher aggregation propensity of Aβ42 over Aβ40, which is in agreement with the experiments. On the basis of the structural features of APS, we propose a plausible aggregation mechanism from APS of Aβ42 to form fibril. The structural and mechanistic observations based on these simulations agree with the recent NMR experiments and provide the driving force and structural origin for the Aβ42 aggregation process to cause AD. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011 相似文献
16.
In this work, peripheral or nonperipheral tetra‐[4‐(9H‐carbazol‐9‐yl)phenoxy] substituted cobalt(II), manganese (III) phthalocyanines were synthesized for the first time. Their acetylcholinesterase from Electrophorus electricus (AChE), butyrylcholinesterase equine serum (BuChE), and α‐glucosidase Saccharomyces cerevisiae inhibition were investigated spectrophotometrically. Finally, in vitro cytotoxicities of the compounds were investigated on human neuroblastoma (SH‐SY5Y) cell line using MTT cell viability assay. The compounds inhibited to enzymes in the range of 7.39 ± 0.25–35.29 ± 2.49 μM with IC50 values for AChE and 14.38 ± 0.66–58.02 ± 4.94 μM for BuChE as compared with galantamine, which used as a positive control. For α‐glucosidase, all compounds had stronger inhibition action than acarbose according to the IC50 values. The IC50 values of N? Co and N? Mn were found to be 3.05 ± 0.10 and 15.82 ± 1.85 μM, respectively. The results of cytotoxicity showed that the IC50 values were above 100 μM showing the compounds had low cytotoxic action against SH‐SY5Y cell line for 24 h. Overall, carbazole substituted nonperipheral compounds can be considered as a potential agent for the treatment of Alzheimer's diseases and diabetes mellitus. 相似文献
17.
A capillary electrophoresis method with in‐column light‐emitting diode induced fluorescence detection is described for simultaneous determination of D ,L ‐serine in the midbrain of a Parkinson's disease mouse. D ,L ‐Serine was derivatized with fluorescein isothiocyanate, and chiral separation and determination of D ,L ‐serine derivatives were performed on a laboratory‐built capillary electrophoresis system with in‐column light‐emitting diode induced fluorescence detector using γ‐cyclodextrin as chiral selector. Using this method, the levels of D ‐ and L ‐serine in the midbrains of Parkinson's disease mice were determined. When compared to controls, the levels of D ‐ and L ‐serine showed significant differences. The result suggested that the biosynthesis and the transportation of endogenous D ,L ‐serine may participate in Parkinson's disease pathogenesis. 相似文献
18.
Nicolas Rouleau William L. Cantley Volha Liaudanskaya Alexander Berk Chuang Du William Rusk Emily Peirent Cole Koester Thomas J. F. Nieland David L. Kaplan 《Macromolecular bioscience》2020,20(3)
The prevalence of dementia and other neurodegenerative diseases continues to rise as age demographics in the population shift, inspiring the development of long‐term tissue culture systems with which to study chronic brain disease. Here, it is investigated whether a 3D bioengineered neural tissue model derived from human induced pluripotent stem cells (hiPSCs) can remain stable and functional for multiple years in culture. Silk‐based scaffolds are seeded with neurons and glial cells derived from hiPSCs supplied by human donors who are either healthy or have been diagnosed with Alzheimer's disease. Cell retention and markers of stress remain stable for over 2 years. Diseased samples display decreased spontaneous electrical activity and a subset displays sporadic‐like indicators of increased pathological β‐amyloid and tau markers characteristic of Alzheimer's disease with concomitant increases in oxidative stress. It can be concluded that the long‐term stability of the platform is suited to study chronic brain disease including neurodegeneration. 相似文献
19.
Supramolecular Modulation of Structural Polymorphism in Pathogenic α‐Synuclein Fibrils Using Copper(II) Coordination
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Tae Su Choi Jeeyoung Lee Jong Yoon Han Byung Chul Jung Piriya Wongkongkathep Joseph A. Loo Min Jae Lee Hugh I. Kim 《Angewandte Chemie (International ed. in English)》2018,57(12):3099-3103
Structural variation of α‐synuclein (αSyn) fibrils has been linked to the diverse etiologies of synucleinopathies. However, little is known about what specific mechanism provides αSyn fibrils with pathologic features. Herein, we demonstrate Cu(II)‐based supramolecular approach for unraveling the formation process of pathogenic αSyn fibrils and its application in a neurotoxic mechanism study. The conformation of αSyn monomer was strained by macrochelation with Cu(II), thereby disrupting the fibril elongation while promoting its nucleation. This non‐canonical process formed shortened, β‐sheet enriched αSyn fibrils (<0.2 μm) that were rapidly transmitted and accumulated to neuronal cells, causing neuronal cell death, in sharp contrast to typical αSyn fibrils (ca. 1 μm). Our approach provided the supramolecular basis for the formation of pathogenic fibrils through physiological factors, such as brain Cu(II). 相似文献
20.
Tatsuya Ikenoue Prof. Dr. Young‐Ho Lee Prof. Dr. József Kardos Miyu Saiki Prof. Dr. Hisashi Yagi Prof. Dr. Yasushi Kawata Prof. Dr. Yuji Goto 《Angewandte Chemie (International ed. in English)》2014,53(30):7799-7804
Although amyloid fibrils are associated with numerous pathologies, their conformational stability remains largely unclear. Herein, we probe the thermal stability of various amyloid fibrils. α‐Synuclein fibrils cold‐denatured to monomers at 0–20 °C and heat‐denatured at 60–110 °C. Meanwhile, the fibrils of β2‐microglobulin, Alzheimer’s Aβ1‐40/Aβ1‐42 peptides, and insulin exhibited only heat denaturation, although they showed a decrease in stability at low temperature. A comparison of structural parameters with positive enthalpy and heat capacity changes which showed opposite signs to protein folding suggested that the burial of charged residues in fibril cores contributed to the cold denaturation of α‐synuclein fibrils. We propose that although cold‐denaturation is common to both native proteins and misfolded fibrillar states, the main‐chain dominated amyloid structures may explain amyloid‐specific cold denaturation arising from the unfavorable burial of charged side‐chains in fibril cores. 相似文献