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1.
Dan‐Jing Yang Shuo Shi Leng‐Feng Zheng Tian‐Ming Yao Liang‐Nian Ji 《Biopolymers》2010,93(12):1100-1107
The loss of metal homeostasis and the toxic effect of metal ion are important events in neurodegenerative and age‐related diseases, such as Alzheimer's disease (AD). For the first time, we investigated the impacts of mercury(II) ions on the folding and aggregation of Alzheimer's tau fragment R2 (residues 275‐305: VQIIN KKLDL SNVQS KCGSK DNIKH VPGGGS), corresponding to the second repeat unit of the microtubule‐binding domain, which was believed to be pivotal to the biochemical properties of full tau protein. By ThS fluorescence assay and electron microscopy, we found that mercury(II) dramatically promoted heparin‐induced aggregation of R2 at an optimum molar ratio of 1: 2 (metal: protein), and the resulting R2 filaments became smaller. Isothermal titration calorimetry (ITC) experiment revealed that the strong coordination of mercury(II) with R2 was an enthalpy‐controlled, entropy‐decreased thermodynamic process. The exceptionally large magnitude of heat release (ΔH1 = ?34.8 Kcal mol?1) suggested that the most possible coordinating site on the R2 peptide chain was the thiol group of cysteine residue (Cys291), and this was further confirmed by a control experiment using Cys291 mutated R2. Circular dichroism spectrum demonstrated that this peptide underwent a significant conformational change from random coil to β‐turn structure upon its binding to mercury(II) ion. This study was undertaken to better understand the mechanism of tau aggregation, and evaluate the possible role of mercury(II) in the pathogenesis of AD. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 1100–1107, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com 相似文献
2.
Abstract
The ability of a polypeptide to fold into a unique, functional, and three-dimensional structure depends on the intrinsic properties of the amino acid sequence, function of the molecular chaperones, proteins, and enzymes. Every polypeptide has a finite tendency to misfold and this forms the darker side of the protein world. Partially folded and misfolded proteins that escape the cellular quality control mechanism have the high tendency to form inter-molecular hydrogen bonding between the same protein molecules resulting in aggregation. This review summarizes the underlying and universal mechanism of protein folding. It also deals with the factors responsible for protein misfolding and aggregation. This article describes some of the consequences of such behavior particularly in the context of neurodegenerative conformational diseases such as Alzheimer’s, Parkinson’s, Huntington’s, amyotrophic lateral sclerosis and other non-neurodegenerative conformational diseases such as cancer and cystic fibrosis etc. This will encourage a more proactive approach to the early diagnosis of conformational diseases and nutritional counseling for patients. 相似文献3.
Environmental exposure to some heavy metals such as cadmium appears to be a risk factor for Alzheimer's disease (AD), however, definite mechanism of their toxicity in AD remains to be elucidated. Previous studies largely focused on the metal ions binding to beta-amyloid, however, very few papers concerned the interaction between tau and metal ions. For the first time, we investigated the impacts of Cd(II) on the conformation and self-aggregation of Alzheimer's tau peptide R3, corresponding to the third repeat of microtubule-binding domain. The initial state of R3 was proven to be dimeric linked by intermolecular disulfide bond, in the non-reducing buffer (Tris-HCl buffer pH7.5, containing no reducing reagent). In this paper, we show that Cd(II) can accelerate heparin-induced aggregation of R3 or independently induce the aggregation of R3, as monitored by ThS fluorescence. In the presence of Cd(II), the resulting R3 filaments became much smaller, as revealed by electron microscopy. Binding to the Cd(II) ion, the dimeric R3 partially lost its random coil, and converted to alpha-helix structure, as revealed by CD and Raman spectrum. Stoichiometric analysis of CD signal against the ratio of [Cd(II)]/[R3] suggested that the coordination intermediate consisted of two R3 dimers binding to a central cadmium ion. As the seed, the coordination intermediate could extensively accelerate the self-aggregation of R3 via promoting the nucleation step. On the other hand, gain in alpha-helix structure on the peptide chain, by coordinating with Cd(II), could be a critical role to promote self-aggregation, as revealed by Raman spectrum. These results provide a further insight into the mechanism of tau filament formation and emphasize the possible involvement of Cd(II) in the pathogenesis of AD. 相似文献
4.
Alzheimer’s disease is characterised by the inappropriate death of brain cells and accumulation of the Aβ peptide in the brain.
Thus, it is possible that there are fundamental differences between Alzheimer’s disease patients and healthy individuals in
their abilities to clear Aβ from brain fluid and to protect neurons from Aβ toxicity. In the present study, we examined (1)
the cytotoxicity of Alzheimer’s disease cerebrospinal fluid (CSF) compared to control CSF, (2) the ability of Alzheimer’s
disease and control CSF to protect cells from Aβ toxicity and to promote cell-mediated clearance of Aβ and lastly (3) the
effects of extracellular chaperones, normally found in CSF, on these processes. We show that the Alzheimer’s disease CSF samples
tested were more toxic to cultured neuroblastoma cells than normal CSF. In addition, the Alzheimer’s disease CSF samples tested
were less able to protect cells from Aβ-induced toxicity and less efficient at promoting macrophage-like cell uptake when
compared to normal CSF. The addition of physiologically relevant concentrations of the extracellular chaperones, clusterin,
haptoglobin and α2-macroglobulin into CSF protected neuroblastoma cells from Αβ1-42 toxicity and promoted Αβ1-42 uptake in macrophage-like cells. These results suggest that extracellular chaperones are an important element of a system
of extracellular protein folding quality control that protects against Aβ toxicity and accumulation. 相似文献
5.
《Journal of inorganic biochemistry》1986,27(1):65-74
Interaction between l-arabinose and the zinc group metal-ion salts has been studied in aqueous solution and solid complexes of the type M(l-arabinose)X2·nH2O, where M = Zn(II), Cd(II), and Hg(II) ions, X = Cl− or Br−, and n = 0–2 have been isolated and characterized. On comparison with the structurally known Ca(l-arabinose) Cl2·4H2O and the corresponding magnesium compounds, it is concluded that the Zn(II) and Cd(II) ions are six-coordinated, binding to two arabinose moieties via 03, 04 of the first and 01, 05 of the second sugar molecule as well as to two H2O molecules. The Hg(II) ion binds only to two sugar molecules in a similar fashion to zinc and cadmium ions, resulting in a four coordination around the mercury ion. The strong intermolecular hydrogen bonding network of the free arabinose is rearranged to that of the sugar OH...H2O...halide system upon metalation. The β-anomer sugar conformation is predominant in the free sugar, while the α-anomer conformation is preferred by the alkaline earth and Zn(II), Cd(II), and Hg(II) cations. 相似文献
6.
Qian Huang Maria E. Figueiredo-Pereira 《Apoptosis : an international journal on programmed cell death》2010,15(11):1292-1311
The ubiquitin/proteasome pathway is the major proteolytic quality control system in cells. In this review we discuss the impact
of a deregulation of this pathway on neuronal function and its causal relationship to the intracellular deposition of ubiquitin
protein conjugates in pathological inclusion bodies in all the major chronic neurodegenerative disorders, such as Alzheimer’s,
Parkinson’s and Huntington’s diseases as well as amyotrophic lateral sclerosis. We describe the intricate nature of the ubiquitin/proteasome
pathway and discuss the paradox of protein aggregation, i.e. its potential toxic/protective effect in neurodegeneration. The
relations between some of the dysfunctional components of the pathway and neurodegeneration are presented. We highlight possible
ubiquitin/proteasome pathway-targeting therapeutic approaches, such as activating the proteasome, enhancing ubiquitination
and promoting SUMOylation that might be important to slow/treat the progression of neurodegeneration. Finally, a model time
line is presented for neurodegeneration starting at the initial injurious events up to protein aggregation and cell death,
with potential time points for therapeutic intervention. 相似文献
7.
A. R. Koudinov N. V. Koudinova E. V. Kezlya K. M. Kozirev A. E. Medvedev T. T. Berezov 《Biochemistry (Moscow) Supplemental Series B: Biomedical Chemistry》2012,6(1):1-10
In-depth scholar literature analysis of Alzheimer’s disease neurodegenerative features of amyloid beta protein neurochemistry
modification and excessive phosphorylation of tau protein (and associated neuronal cytoskeleton rearrangements) are secondary
phenomena. At early disease stage these neurobiochemical mechanisms are reversible and serve to heal an impairment of biophysical
properties of neuronal membranes, neurotransmission, basic neuronal function and neuroplasticity, while preserving anatomical
and functional brain fields. Aβ and tau could well serve to biochemically restore physico-chemical properties of neual membranes
due to a role these proteins play in lipid metabolism. Under such scenario therapeutic block of aggregation and plaque formation
of Aβ and inhibition of tau phosphorylation, as well as pharmaceutical modification of other secondary neurodegenerative features
(such as a cascade of oxidative stress reactions) are unable to provide an effective cure of Alzheimer’s disease and related
pathologies of the Central and peripheral nervous systems, because they are not arraying primary pathagenetic cause. We review
the role of Aβ in compensatory mechanisms of neuroplasticity restoration under normal physiological condition and Alzheimer’s
disease. 相似文献
8.
Alzheimer’s disease is an irreversible, progressive neurodegenerative disorder leading invariably to death, usually within
7–10 years after diagnosis and is the leading cause of dementia in the elderly. Not only is Alzheimer’s disease a tragic disease
in which people suffer from neurodegeneration in the years to come, it also becomes an incredible burden on the public health
system. However, there is currently no effective treatment to halt the progression or prevent the onset of Alzheimer’s disease.
This is partly due to the fact that the complex pathophysiology of Alzheimer’s disease is not yet completely understood. Recently,
Golgi apparatus is found to play an important role in Alzheimer’s disease. In this review, we discuss the changes of Golgi
apparatus during clinical progression and pathological development of Alzheimer’s disease. First, changes of Golgi apparatus
size in Alzheimer’s disease are summarized. We then address the role of Golgi apparatus in the neuropathology of Alzheimer’s
disease. Finally, the role of Golgi apparatus in the pathogenesis of Alzheimer’s disease is discussed. Understanding the contribution
of Golgi apparatus dysfunction to Alzheimer’s disease and its pathophysiological basis will significantly impact our ability
to develop more effective therapies for Alzheimer’s disease. 相似文献
9.
Pasquale Palladino Luisa Ronga Ettore Benedetti Filomena Rossi Raffaele Ragone 《International journal of peptide research and therapeutics》2009,15(3):165-176
The mechanism that underlies a multitude of human disorders, including type II diabetes, Parkinson’s, Huntington’s and Alzheimer’s,
and the prion encephalopathies, is β-structure expansion through a pathogenic aggregation-prone monomeric form. β-sheet expansion
disorders share intermolecular association as a common determinant, being therefore collectively identified as conformational
diseases, but little is known about the underlying mechanism. Transmissible spongiform encephalopathies, also known as prion
diseases, are all characterised by progressive neuronal degeneration associated to marked extracellular accumulation of an
amyloidogenic conformer of the normal cellular prion protein (PrPC), referred to as the scrapie isoform (PrPSc), which is thought to be responsible for the disease symptoms. PrPC is a ubiquitous 231-amino acid glycoprotein, whose physiological role is still elusive. It is organised as an N-terminal
disordered region and a compact C-terminal domain, where secondary structure elements consist of three α-helices (α1, α2 and
α3), with an α2-α3 disulphide bridge, and two short β-strands (β1 and β2). Evidence accumulated so far suggests that the protein
possesses one or several ‘spots’ of intrinsic conformational weakness, which may trigger generic folding, leading the whole
architecture to adopt aggregation-prone conformations. One of such spots is suspected to be the C-terminal side of the α-helix
2, which has recently gained the attention of several investigations because it gathers several disease-associated point mutations,
can be strongly fibrillogenic and toxic to neuronal cells, and possesses chameleon conformational behaviour. This paper briefly
reviews recent literature on α-2 domain-derived model peptides. 相似文献
10.
Aggregation of the amyloid β-peptide (Aβ) into insoluble fibrils is a key pathological event in Alzheimer’s disease. Cu(II)
and Zn(II) ions were reported to be able to induce Aβ aggregation at nearly physiological concentrations in vitro. In this
study, the binding modes of Cu(II) and Zn(II) in this process were explored by molecular modeling. In the pre-associated Aβ,
Nτ atom of imidazole ring of His14, O atom of carbonyl of main-chain and two O atoms of water occupied the four ligand positions
of the complex. While in the aggregated form of Aβ, the His13(N)–Metals–His14(N) bridges were formed through metal cross-linking
action. These results would be helpful to put insight on revealing the formation mechanism of pathogenic Aβ aggregates in
brain. 相似文献
11.
David C. Rubinsztein 《Mammalian genome》2008,19(9):587-590
Many of the neurodegenerative diseases that afflict humans are characterised by the protein aggregation in neurons. These
include complex diseases like Alzheimer’s disease and Parkinson’s disease, and Mendelian diseases caused by polyglutamine
expansion mutations [like Huntington’s disease (HD) and various spinocerebellar ataxias (SCAs), like SCA3]. A range of functional
genomic strategies have been used to try to elucidate pathways involved in these diseases. In this minireview, I focus on
how modifier screens in organisms from yeast to mice may be of value in helping to elucidate pathogenic pathways. 相似文献
12.
P. Eikelenboom J. M. Rozemuller G. Kraal F. C. Stam P. A. McBride M. E. Bruce H. Fraser 《Virchows Archiv. B, Cell pathology including molecular pathology》1991,60(1):329-336
Complement proteins of the classical pathway can be immunohistochemically identified in cerebral amyloid plaques in Alzheimer’s
disease. Microglial cells in and around amyloid plaques express class II major histocompatibility (MHC) antigens and complement
receptors CR3 and CR4. Negative immunostaining for immunoglobulins and for T-cell subsets in the brain parenchyma demonstrates
a lack of evidence for the involvement of specific immune responses (such as an immune complex-mediated complement activation
or a cell-mediated immune response) in cerebral amyloid deposits in Alzheimer’s disease. Cerebral amyloid plaques in scrapie-affected
mice (slow-virus induced encephalopathy) do not contain complement factors C1q and C3c and are not clustered with microglial
cells expressing MHC class II molecules or complement receptor CR3. The data presented suggest the induction of a reactive
inflammatory process by β/A4 amyloid in the human brain, but not by scrapie-induced PrP amyloid in mice. Our findings do not
support the hypothesis that the immune system is involved in the generation of amyloid plaques in Alzheimer’s disease.
This study was partly supported by a grant from the Praeventiefonds, project 28–1945 相似文献
13.
The pathologic lesions of Alzheimer’s disease (AD) are characterized by accumulation of protein aggregates consisting of intracellular
or extracellular misfolded proteins. The amyloid-β (Aβ) protein accumulates extracellularly in senile plaques and cerebral
amyloid angiopathy, whereas the hyperphosphorylated tau protein accumulates intracellularly as neurofibrillary tangles. “Professional
chaperones”, such as the heat shock protein family, have a function in the prevention of protein misfolding and subsequent
aggregation. “Amateur” chaperones, such as apolipoproteins and heparan sulfate proteoglycans, bind amyloidogenic proteins
and may affect their aggregation process. Professional and amateur chaperones not only colocalize with the pathological lesions
of AD, but may also be involved in conformational changes of Aβ, and in the clearance of Aβ from the brain via phagocytosis
or active transport across the blood–brain barrier. Thus, both professional and amateur chaperones may be involved in the
aggregation, accumulation, persistence, and clearance of Aβ and tau and in other Aβ-associated reactions such as inflammation
associated with AD lesions, and may, therefore, serve as potential targets for therapeutic intervention. 相似文献
14.
The abnormal assembly and deposition of specific proteins in the brain is the probable cause of most neurodegenerative disease
afflicting the elderly. These “cerebral proteopathies” include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s
disease (HD), prion diseases, and a variety of other disorders. Evidence is accumulating that the anomalous aggregation of
the proteins, and not a loss of protein function, is central to the pathogenesis of these diseases. Thus, therapeutic strategies
that reduce the production, accumulation, or polymerization of pathogenic proteins might be applicable to a wide range of
some of the most devastating diseases of old age. 相似文献
15.
A. V. Maltsev O. V. Galzitskaya 《Biochemistry (Moscow) Supplemental Series B: Biomedical Chemistry》2010,4(3):228-236
Studies of neurodegenerative disorders attract much attention of the world scientific community due to increasing dissemination
of Alzheimer’s disease. The reason for such pathologies consists in transition of a “healthy” molecule or peptide from its
native conformation into a very stable “pathological” form. During this process, molecules existing in the “pathological”
conformation aggregate and form amyloid fibrils that can undergo an uncontrolled increase. Novel knowledge is required on
sporadic forms of Alzheimer’s disease, on the nature of triggering mechanisms of the conformational transitions of beta-amyloid
fragments from normally functioning proteins into new structure, nano-beta-amyloids, that escape of neuronal and whole-body
control resulted in the loss of neurons. This review summarized results of studies on the formation of amyloid fibrils and
their role in pathogenesis of amyloid diseases. 相似文献
16.
《Carbohydrate research》1988,172(1):1-10
Interaction of β-d-fructose with hydrated salts of zinc-group-metal has been studied in aqueous solution and solid adducts of the type M(d-fructose)X2·nH2O, where M = Zn(II), Cd(II), and Hg(II) ions, X = Cl− or Br−, and n = 0–2, have been isolated, and characterized by means of F.t.-i.r. spectroscopy, X-ray powder diffraction, and molar conductivity measurements. The marked spectral similarities observed with the Mg(d-fructose)X2·4 H2O (X = Cl− or Br−) compounds indicated that the Zn(II) and Cd(II) ions are six-coordinated, binding to two d-fructose molecules through O-2, O-3 of the first d-fructose, and O-4, O-5 of the second, as well as to two H2O. The Hg(II) ion binds to two sugar moieties in the same fashion as do the Zn(II) and Cd(II) ions, resulting in four-coordination geometry around the mercury ion. The crystalline sugar is in the β-d-fructopyranose form, and the coordination of the of the Ca(II) ion takes place through the β-d-fructopyranose isomer, whereas the binding of the Mg(II), Zn(II), Cd(II), Hg(II), and UO2+2 cations could be via the β-d-fructopyranose and the β-d-fructofuranose structures. 相似文献
17.
Bernal-Uruchurtu MI Metta-Magaña AJ Guerrero-Álvarez JA Reyes-Martínez R Tlahuext H 《Carbohydrate research》2008,343(16):2804-2812
The reactivity of N-(2-aminophenyl)-d-glycero-d-gulo-heptonamide (adgha), with the group 12 cations, Zn(II), Cd(II), and Hg(II), was studied in DMSO-d6 solution. The studied system showed a selective coordination to Hg(II), and the products formed were characterized by 1H and 13C NMR in DMSO-d6 solution and fast atom bombardment (FAB+) mass spectra. The expected coordination compounds, [Hg(adgha)](NO3)2 and [Hg(adgha)2](NO3)2, were observed as unstable intermediates that decompose to bis-[2-(d-glycero-d-gulo-hexahydroxyhexyl)-benzimidazole-κN]mercury(II) dinitrate, [Hg(ghbz)2](NO3)2. The chemical transformation of the complexes was followed by NMR experiments, and the nature of the species formed is sustained by a theoretical study done using DFT methodology. From this study, we propose the structure of the complexes formed in solution, the relative stability of the species formed, and the possible role of the solvent in the observed transformations. 相似文献
18.
The use of acetylcholinesterase inhibitors to decrease the breakdown of the neurotransmitter acetylcholine has been the main
symptomatic therapy for mild to moderate Alzheimer’s patients, though the etiology of Alzheimer’s disease remains unclear
and seems to involve multiple factors. Further evidence has indicated that some of these acetylcholinesterase inhibitors also
have non-cholinergic functions on the pathogenesis of Alzheimer’s disease including the formation and deposition of β-amyloid.
Huperzine A, a potent and reversible inhibitor of acetylcholinesterase that was initially isolated from a Chinese herb, has
been found to improve cognitive deficits in a broad range of animal models and has been used for Alzheimer’s disease treatment
in China. The novel neuroprotective effects of huperzine A might yield beneficial effects in Alzheimer’s disease therapy and
provide a potential template for the design of new selective and powerful anti-Alzheimer’s drugs. The present paper gives
an overview on the neuroprotective effects of huperzine A beyond its acetylcholinesterase inhibition. These effects include
regulating β-amyloid precursor protein metabolism, protecting against β-amyloid-mediated oxidative stress and apoptosis. The
structure–function relationship of huperzine A is also discussed. 相似文献
19.
Münch C Zhu BG Mink A Seefried U Riepe MW Ludolph AC Meyer T 《Neurochemical research》2008,33(6):1005-1010
Hypoxia is one of the major common components of vascular risk factors for pathogenesis of Alzheimer’s disease. This study
investigated the possible relationship between hypoxia and alternative splicing of the excitatory amino acid transporter 2
(EAAT2) in a transgenic model for Alzheimer’s disease. We used an APP23 mouse model prior to amyloid deposition and subjected
it to chemical hypoxia treatment as induced by 3-nitropropionic acid. One hour after administration of 3-nitropropionic acid
changes in the expression of the 5′-splice forms mEAAT2/5UT3, mEAAT2/5UT4, and mEAAT2/5UT5 were found in the frontal cortex,
hippocampus and cerebellum of the APP23 model. In untreated APP23 animals the expression of EAAT2 splice variants was unchanged.
Our results demonstrate that hypoxia facilitates alternative splicing of EAAT2 in the APP23 model. This may be a molecular
mechanism linking vascular factors to early pathophysiology of Alzheimer’s disease. 相似文献
20.
Metals ions and neurodegeneration 总被引:4,自引:0,他引:4
Francisco Molina-Holgado Robert C. Hider Alessandra Gaeta Robert Williams Paul Francis 《Biometals》2007,20(3-4):639-654
Neurodegenerative disorders include a variety of pathological conditions, which share similar critical metabolic processes
such as protein aggregation and oxidative stress, both of which are associated with the involvement of metal ions. In this
review Alzheimer’s disease and Parkinson’s disease are mainly discussed, with the aim of identifying common trends underlying
these neurological conditions. Chelation therapy could be a valuable therapeutic approach, since metals are considered to
be a pharmacological target for the rationale design of new therapeutic agents directed towards the treatment of neurodegeneration. 相似文献