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Exploring the Release of Toxic Oligomers from α-Synuclein Fibrils with Antibodies and STED Microscopy.
α-Synuclein (αS) is an intrinsically disordered and highly dynamic protein involved in dopamine release at presynaptic terminals. The abnormal aggregation of αS as mature fibrils into intraneuronal inclusion bodies is directly linked to Parkinson's disease. Increasing experimental evidence suggests that soluble oligomers formed early during the aggregation process are the most cytotoxic forms of αS. This study investigated the uptake by neuronal cells of pathologically relevant αS oligomers and fibrils exploiting a range of conformation-sensitive antibodies, and the super-resolution stimulated emission depletion (STED) microscopy. We found that prefibrillar oligomers promptly penetrate neuronal membranes, thus resulting in cell dysfunction. By contrast, fibril docking to the phospholipid bilayer is accompanied by αS conformational changes with a progressive release of A11-reactive oligomers, which can enter into the neurons and trigger cell impairment. Our data provide important evidence on the role of αS fibrils as a source of harmful oligomers, which resemble the intermediate conformers formed de novo during aggregation, underling the dynamic and reversible nature of protein aggregates responsible for α-synucleinopathies
The pseudogap state in superconductors: Extended Hartree approach to time-dependent Ginzburg-Landau Theory
It is well known that conventional pairing fluctuation theory at the Hartree
level leads to a normal state pseudogap in the fermionic spectrum. Our goal is
to extend this Hartree approximated scheme to arrive at a generalized mean
field theory of pseudogapped superconductors for all temperatures . While an
equivalent approach to the pseudogap has been derived elsewhere using a more
formal Green's function decoupling scheme, in this paper we re-interpret this
mean field theory and BCS theory as well, and demonstrate how they naturally
relate to ideal Bose gas condensation. Here we recast the Hartree approximated
Ginzburg-Landau self consistent equations in a T-matrix form. This recasting
makes it possible to consider arbitrarily strong attractive coupling, where
bosonic degrees of freedom appear at considerably above . The
implications for transport both above and below are discussed. Below
we find two types of contributions. Those associated with fermionic
excitations have the usual BCS functional form. That they depend on the
magnitude of the excitation gap, nevertheless, leads to rather atypical
transport properties in the strong coupling limit, where this gap (as distinct
from the order parameter) is virtually -independent. In addition, there are
bosonic terms arising from non-condensed pairs whose transport properties are
shown here to be reasonably well described by an effective time-dependent
Ginzburg-Landau theory.Comment: 14 pages, 5 figures, REVTeX4, submitted to PRB; clarification of the
diagrammatic technique added, one figure update
Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease
Protein aggregation and oxidative stress are both key pathogenic processes in Parkinson's disease, although the mechanism by which misfolded proteins induce oxidative stress and neuronal death remains unknown. In this study, we describe how aggregation of alpha-synuclein (α-S) from its monomeric form to its soluble oligomeric state results in aberrant free radical production and neuronal toxicity
The release of toxic oligomers from α-synuclein fibrils induces dysfunction in neuronal cells.
The self-assembly of α-synuclein (αS) into intraneuronal inclusion bodies is a key characteristic of Parkinson's disease. To define the nature of the species giving rise to neuronal damage, we have investigated the mechanism of action of the main αS populations that have been observed to form progressively during fibril growth. The αS fibrils release soluble prefibrillar oligomeric species with cross-β structure and solvent-exposed hydrophobic clusters. αS prefibrillar oligomers are efficient in crossing and permeabilize neuronal membranes, causing cellular insults. Short fibrils are more neurotoxic than long fibrils due to the higher proportion of fibrillar ends, resulting in a rapid release of oligomers. The kinetics of released αS oligomers match the observed kinetics of toxicity in cellular systems. In addition to previous evidence that αS fibrils can spread in different brain areas, our in vitro results reveal that αS fibrils can also release oligomeric species responsible for an immediate dysfunction of the neurons in the vicinity of these species
Amyloid-β and α-Synuclein Decrease the Level of Metal-Catalyzed Reactive Oxygen Species by Radical Scavenging and Redox Silencing.
The formation of reactive oxygen species (ROS) is linked to the pathogenesis of neurodegenerative diseases. Here we have investigated the effect of soluble and aggregated amyloid-β (Aβ) and α-synuclein (αS), associated with Alzheimer's and Parkinson's diseases, respectively, on the Cu(2+)-catalyzed formation of ROS in vitro in the presence of a biological reductant. We find that the levels of ROS, and the rate by which ROS is generated, are significantly reduced when Cu(2+) is bound to Aβ or αS, particularly when they are in their oligomeric or fibrillar forms. This effect is attributed to a combination of radical scavenging and redox silencing mechanisms. Our findings suggest that the increase in ROS associated with the accumulation of aggregated Aβ or αS does not result from a particularly ROS-active form of these peptides, but rather from either a local increase of Cu(2+) and other ROS-active metal ions in the aggregates or as a downstream consequence of the formation of the pathological amyloid structures.This work was supported by the Villum Foundation (J.T.P., L.H.), the Lundbeck Foundation (J.T.P., K.T.), the Agency for Science, Technology and Research, Singapore (S.W.C.), The Wellcome Trust (C.M.D.) and the Spanish Ministry of Economy and Competitiveness through the Ramon y Cajal ́ program (N.C.).This is the final version of the article. It first appeared from the American Chemical Society via http://dx.doi.org/10.1021/jacs.5b1357
Intestinal fungi contribute to development of alcoholic liver disease
This study was supported in part by NIH grants R01 AA020703, U01 AA021856 and by Award Number I01BX002213 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (to B.S.). K.H. was supported by a DFG (Deutsche Forschungsgemeinschaft) fellowship (HO/ 5690/1-1). S.B. was supported by a grant from the Swiss National Science Foundation (P2SKP3_158649). G.G. received funding from the Yale Liver Center NIH P30 DK34989 and R.B. from NIAAA grant U01 AA021908. A.K. received support from NIH grants RC2 AA019405, R01 AA020216 and R01 AA023417. G.D.B. is supported by funds from the Wellcome Trust. We acknowledge the Human Tissue and Cell Research (HTCR) Foundation for making human tissue available for research and Hepacult GmbH (Munich, Germany) for providing primary human hepatocytes for in vitro analyses. We thank Dr. Chien-Yu Lin Department of Medicine, Fu-Jen Catholic University, Taiwan for statistical analysis.Peer reviewedPublisher PD
On the Relationship Between the Pseudo- and Superconducting Gaps: Effects of Residual Pairing Correlations Below Tc
The existence of a normal state spectral gap in underdoped cuprates raises
important questions about the associated superconducting phase. For example,
how does this pseudogap evolve into its below Tc counterpart? In this paper we
characterize this unusual superconductor by investigating the nature of the
``residual'' pseudogap below Tc and, find that it leads to an important
distinction between the superconducting excitation gap and order parameter. Our
approach is based on a conserving diagrammatic BCS Bose-Einstein crossover
theory which yields the precise BCS result in weak coupling at any T<Tc and
reproduces Leggett's results in the T=0 limit. We explore the resulting
experimental implications.Comment: REVTeX, 4 pages, 1 EPS figure (included
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