scholarly journals Ionic Environment Affects Biomolecular Interactions of Amyloid-β: SPR Biosensor Study

2020 ◽  
Vol 21 (24) ◽  
pp. 9727
Author(s):  
Erika Hemmerová ◽  
Tomáš Špringer ◽  
Zdeňka Krištofiková ◽  
Jiří Homola
Keyword(s):  
Physiological State ◽  
Amyloid Β ◽  
Mitochondrial Proteins ◽  
Biomolecular Interactions ◽  
Mitochondrial Matrix ◽  
Cyclophilin D ◽  
Ionic Environment ◽  
Spr Biosensor ◽  
Multiple Processes ◽  
Associated Conditions

In early stages of Alzheimer’s disease (AD), amyloid beta (Aβ) accumulates in the mitochondrial matrix and interacts with mitochondrial proteins, such as cyclophilin D (cypD) and 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10). Multiple processes associated with AD such as increased production or oligomerization of Aβ affect these interactions and disbalance the equilibrium between the biomolecules, which contributes to mitochondrial dysfunction. Here, we investigate the effect of the ionic environment on the interactions of Aβ (Aβ1–40, Aβ1–42) with cypD and 17β-HSD10 using a surface plasmon resonance (SPR) biosensor. We show that changes in concentrations of K+ and Mg2+ significantly affect the interactions and may increase the binding efficiency between the biomolecules by up to 35% and 65% for the interactions with Aβ1–40 and Aβ1–42, respectively, in comparison with the physiological state. We also demonstrate that while the binding of Aβ1–40 to cypD and 17β-HSD10 takes place preferentially around the physiological concentrations of ions, decreased concentrations of K+ and increased concentrations of Mg2+ promote the interaction of both mitochondrial proteins with Aβ1–42. These results suggest that the ionic environment represents an important factor that should be considered in the investigation of biomolecular interactions taking place in the mitochondrial matrix under physiological as well as AD-associated conditions.

Conformational characterization of nucleosome structure by Electron Microscopy

1993 ◽  
Vol 51 ◽  
pp. 194-195
Author(s):  
Gregory J. Czarnota
Keyword(s):  
Electron Microscopy ◽  
Structural Changes ◽  
Physiological State ◽  
Gene Activation ◽  
Three Dimensional ◽  
Macromolecular Complex ◽  
Ultrastructural Studies ◽  
Ionic Environment ◽  
Nucleosome Structure ◽  
Dimensional Reconstruction

Chromatin structure at the fundamental level of the nucleosome is important in vital cellular processes. Recent biochemical and genetic analyses show that nucleosome structure and structural changes are very active participants in gene expression, facilitating or inhibiting transcription and reflecting the physiological state of the cell. Structural states and transitions for this macromolecular complex, composed of DNA wound about a heterotypic octamer of variously modified histone proteins, have been measured by physico-chemical techniques and by enzyme-accessibility and are recognized to occur with various post-translational modifications, gene activation, transformation and with ionic-environment. In spite of studies which indicate various forms of nucleosome structure, all current x-ray and neutron diffraction studies have consistently resulted in only one structure, suggestive of a static conformation. In contrast, two-dimensional electron microscopy studies and three-dimensional reconstruction techniques have yielded different structures. These fundamental differences between EM and other ultrastructural studies have created a long standing quandary, which I have addressed and resolved using spectroscopic electron microscopy and statistical analyses of nucleosome images in a study of nucleosome structure with ionic environment.

Amyloid-β Protein Precursor Deficiency Changes Neuronal Electrical Activity and Levels of Mitochondrial Proteins in the Medial Prefrontal Cortex

2021 ◽  
pp. 1-14
Author(s):  
Qingwei Huo ◽  
Sidra Tabassum ◽  
Ming Chen ◽  
Mengyao Sun ◽  
Yueming Deng ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Amyloid Β ◽  
Neuronal Firing ◽  
Mitochondrial Proteins ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein ◽  
Neuronal Electrical Activity

Background: Neuropathological features of Alzheimer’s disease are characterized by the deposition of amyloid-β (Aβ) plaques and impairments in synaptic activity and memory. However, we know little about the physiological role of amyloid-β protein precursor (AβPP) from which Aβ derives. Objective: Evaluate APP deficiency induced alterations in neuronal electrical activity and mitochondrial protein expression. Methods: Utilizing electrophysiological, biochemical, pharmacological, and behavioral tests, we revealed aberrant local field potential (LFP), extracellular neuronal firing and levels of mitochondrial proteins. Result: We show that APP knockout (APP -/- ) leads to increased gamma oscillations in the medial prefrontal cortex (mPFC) at 1-2 months old, which can be restored by baclofen (Bac), a γ-aminobutyric acid type B receptor (GABABR) agonist. A higher dose and longer exposure time is required for Bac to suppress neuronal firing in APP -/-  mice than in wild type animals, indicating enhanced GABABR mediated activity in the mPFC of APP -/-  mice. In line with increased GABABR function, the glutamine synthetase inhibitor, L-methionine sulfonate, significantly increases GABABR levels in the mPFC of APP -/-  mice and this is associated with a significantly lower incidence of death. The results suggest that APP -/-  mice developed stronger GABABR mediated inhibition. Using HEK 293 as an expression system, we uncover that AβPP functions to suppress GABABR expression. Furthermore, APP -/-  mice show abnormal expression of several mitochondrial proteins. Conclusion: APP deficiency leads to both abnormal network activity involving defected GABABR and mitochondrial dysfunction, suggesting critical role of AβPP in synaptic and network function.

scholarly journals Solid-phase inclusion as a mechanism for regulating unfolded proteins in the mitochondrial matrix

2020 ◽  
Vol 6 (32) ◽  
pp. eabc7288
Author(s):  
Linhao Ruan ◽  
Joshua T. McNamara ◽  
Xi Zhang ◽  
Alexander Chih-Chieh Chang ◽  
Jin Zhu ◽  
...  
Keyword(s):  
Solid Phase ◽  
Tricarboxylic Acid Cycle ◽  
Yeast Cells ◽  
Mitochondrial Proteins ◽  
Mitochondrial Matrix ◽  
Unfolded Proteins ◽  
Daughter Cells ◽  
Contact Sites ◽  
Age Dependent ◽  
Mother And Daughter

Proteostasis declines with age, characterized by the accumulation of unfolded or damaged proteins. Recent studies suggest that proteins constituting pathological inclusions in neurodegenerative diseases also enter and accumulate in mitochondria. How unfolded proteins are managed within mitochondria remains unclear. Here, we found that excessive unfolded proteins in the mitochondrial matrix of yeast cells are consolidated into solid-phase inclusions, which we term deposits of unfolded mitochondrial proteins (DUMP). Formation of DUMP occurs in mitochondria near endoplasmic reticulum–mitochondria contact sites and is regulated by mitochondrial proteins controlling the production of cytidine 5′-diphosphate–diacylglycerol. DUMP formation is age dependent but accelerated by exogenous unfolded proteins. Many enzymes of the tricarboxylic acid cycle were enriched in DUMP. During yeast cell division, DUMP formation is necessary for asymmetric inheritance of damaged mitochondrial proteins between mother and daughter cells. We provide evidence that DUMP-like structures may be induced by excessive unfolded proteins in human cells.

Inhibition of Aβ(1–40) fibril formation by cyclophilins

2016 ◽  
Vol 473 (10) ◽  
pp. 1355-1368 ◽  
Author(s):  
Marten Villmow ◽  
Monika Baumann ◽  
Miroslav Malesevic ◽  
Rolf Sachs ◽  
Gerd Hause ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Water Soluble ◽  
Main Process ◽  
Amyloid Β Peptide ◽  
Cyclophilin D ◽  
Aβ Amyloid

Cyclophilins interact directly with the Alzheimer's disease peptide Aβ (amyloid β-peptide) and are therefore involved in the early stages of Alzheimer's disease. Aβ binding to CypD (cyclophilin D) induces dysfunction of human mitochondria. We found that both CypD and CypA suppress in vitro fibril formation of Aβ(1–40) at substoichiometric concentrations when present early in the aggregation process. The prototypic inhibitor CsA (cyclosporin A) of both cyclophilins as well as the new water-soluble MM258 derivative prevented this suppression. A SPOT peptide array approach and NMR titration experiments confirmed binding of Aβ(1–40) to the catalytic site of CypD mainly via residues Lys16–Glu22. The peptide Aβ(16–20) representing this section showed submicromolar IC50 values for the peptidyl prolyl cis–trans isomerase activity of CypD and CypA and low-micromolar KD values in ITC experiments. Chemical cross-linking and NMR-detected hydrogen–deuterium exchange experiments revealed a shift in the populations of small Aβ(1–40) oligomers towards the monomeric species, which we investigated in the present study as being the main process of prevention of Aβ fibril formation by cyclophilins.

Automated backbone and side-chain assignment of mitochondrial matrix cyclophilin D

2007 ◽  
Vol 38 (3) ◽  
pp. 267-267 ◽  
Author(s):  
Andreas Schedlbauer ◽  
Bernd Hoffmann ◽  
Georg Kontaxis ◽  
Simon Rüdisser ◽  
Ulrich Hommel ◽  
...  
Keyword(s):  
Side Chain ◽  
Mitochondrial Matrix ◽  
Cyclophilin D

scholarly journals In vitro study of interaction of 17β-hydroxysteroid dehydrogenase type 10 and cyclophilin D and its potential implications for Alzheimer’s disease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Erika Hemmerová ◽  
Tomáš Špringer ◽  
Zdenka Krištofiková ◽  
Jiří Homola
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Permeability Transition ◽  
Amyloid Β ◽  
In Vitro Study ◽  
Permeability Transition ◽  
Stable Complex ◽  
Cyclophilin D ◽  
Permeability Transition Pores

Abstract In early stages of Alzheimer’s disease (AD), amyloid-β (Aβ) accumulates in neuronal mitochondria where it interacts with a number of biomolecules including 17beta-hydroxysteroide dehydrogenase 10 (17β-HSD10) and cyclophilin D (cypD). It has been hypothesized that 17β-HSD10 interacts with cypD preventing it from opening mitochondrial permeability transition pores and that its regulation during AD may be affected by the accumulation of Aβ. In this work, we demonstrate for the first time that 17β-HSD10 and cypD form a stable complex in vitro. Furthermore, we show that factors, such as pH, ionic environment and the presence of Aβ, affect the ability of 17β-HSD10 to bind cypD. We demonstrate that K+ and Mg2+ ions present at low levels may facilitate this binding. We also show that different fragments of Aβ (Aβ1–40 and Aβ1–42) affect the interaction between 17β-HSD10 and cypD differently and that Aβ1–42 (in contrast to Aβ1–40) is capable of simultaneously binding both 17β-HSD10 and cypD in a tri-complex.

scholarly journals Mitochondria, Amyloid β, and Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Ryan D. Readnower ◽  
Andrew D. Sauerbeck ◽  
Patrick G. Sullivan
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Permeability Transition ◽  
Amyloid Β ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Enzymes ◽  
Cyclophilin D ◽  
Ample Evidence

Hypometabolism is a hallmark of Alzheimer's disease (AD) and implicates a mitochondrial role in the neuropathology associated with AD. Mitochondrial amyloid-beta (Aβ) accumulation precedes extracellular Aβdeposition. In addition to increasing oxidative stress, Aβhas been shown to directly inhibit mitochondrial enzymes. Inhibition of mitochondrial enzymes as a result of oxidative damage or Aβinteraction perpetuates oxidative stress and leads to a hypometabolic state. Additionally, Aβhas also been shown to interact with cyclophilin D, a component of the mitochondrial permeability transition pore, which may promote cell death. Therefore, ample evidence exists indicating that the mitochondrion plays a vital role in the pathophysiology observed in AD.

scholarly journals Methylation as a key regulator of Tau aggregation and neuronal health in Alzheimer’s disease

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abhishek Ankur Balmik ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Physiological State ◽  
Regulation Of Gene Expression ◽  
Amyloid Β ◽  
Major Protein ◽  
Cellular Functions ◽  
Global Methylation ◽  
Post Translational Modifications ◽  
Tau Function ◽  
A Site ◽  
Tau Aggregation

AbstractNeurodegenerative diseases like Alzheimer’s, Parkinson’s and Huntington’s disease involves abnormal aggregation and accumulation of toxic proteins aggregates. Post-translational modifications (PTMs) of the causative proteins play an important role in the etiology of disease as they could either slow down or accelerate the disease progression. Alzheimer disease is associated with the aggregation and accumulation of two major protein aggregates—intracellular neurofibrillary tangles made up of microtubule-associated protein Tau and extracellular Amyloid-β plaques. Post-translational modifications are important for the regulation of Tau`s function but an imbalance in PTMs may lead to abnormal Tau function and aggregation. Tau methylation is one of the important PTM of Tau in its physiological state. However, the methylation signature on Tau lysine changes once it acquires pathological aggregated form. Tau methylation can compete with other PTMs such as acetylation and ubiquitination. The state of PTM at these sites determines the fate of Tau protein in terms of its function and stability. The global methylation in neurons, microglia and astrocytes are involved in multiple cellular functions involving their role in epigenetic regulation of gene expression via DNA methylation. Here, we have discussed the effect of methylation on Tau function in a site-specific manner and their cross-talk with other lysine modifications. We have also elaborated the role of methylation in epigenetic aspects and neurodegenerative conditions associated with the imbalance in methylation metabolism affecting global methylation state of cells.

scholarly journals The novel mitochondrial matrix protease Ste23 is required for efficient presequence degradation and processing

2017 ◽  
Vol 28 (8) ◽  
pp. 997-1002 ◽  
Author(s):  
Asli Aras Taskin ◽  
Cansu Kücükköse ◽  
Nils Burger ◽  
Dirk Mossmann ◽  
Chris Meisinger ◽  
...  
Keyword(s):  
Human Insulin ◽  
Feedback Inhibition ◽  
Amyloid Β ◽  
The Novel ◽  
Mitochondrial Matrix ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Precursor Proteins ◽  
The Matrix ◽  
Processing Protease

Approximately 70% of mitochondrial precursor proteins are imported from the cytosol via N-terminal presequences, which are cleaved upon exposure to the mitochondrial processing protease MPP in the matrix. Cleaved presequence peptides then need to be efficiently degraded, and impairment of this clearance step, for example, by amyloid β peptides, causes feedback inhibition of MPP, leading ultimately to accumulation of immature precursor proteins within mitochondria. Degradation of mitochondrial peptides is performed by Cym1 in yeast and its homologue, PreP, in humans. Here we identify the novel mitochondrial matrix protease Ste23 in yeast, a homologue of human insulin-degrading enzyme, which is required for efficient peptide degradation. Ste23 and Cym1 tightly cooperate to ensure the correct functioning of the essential presequence processing machinery.

scholarly journals High-resolution crystal structures of two crystal forms of human cyclophilin D in complex with PEG 400 molecules

2014 ◽  
Vol 70 (6) ◽  
pp. 717-722 ◽  
Author(s):  
Koteswara Rao Valasani ◽  
Emily A. Carlson ◽  
Kevin P. Battaile ◽  
Andrea Bisson ◽  
Chunyu Wang ◽  
...  
Keyword(s):  
High Resolution ◽  
Crystal Structures ◽  
Structural Information ◽  
Amyloid Β ◽  
Crystal Form ◽  
Cyclophilin D ◽  
Crystal Forms ◽  
Peg 400 ◽  
Mitochondrial Target ◽  
Resolution Structure

Cyclophilin D (CypD) is a key mitochondrial target for amyloid-β-induced mitochondrial and synaptic dysfunction and is considered a potential drug target for Alzheimer's disease. The high-resolution crystal structures of primitive orthorhombic (CypD-o) and primitive tetragonal (CypD-t) forms have been determined to 1.45 and 0.85 Å resolution, respectively, and are nearly identical structurally. Although an isomorphous structure of CypD-t has previously been reported, the structure reported here was determined at atomic resolution, while CypD-o represents a new crystal form for this protein. In addition, each crystal form contains a PEG 400 molecule bound to the same region along with a second PEG 400 site in CypD-t which occupies the cyclosporine A inhibitor binding site of CypD. Highly precise structural information for CypD should be extremely useful for discerning the detailed interaction of small molecules, particularly drugs and/or inhibitors, bound to CypD. The 0.85 Å resolution structure of CypD-t is the highest to date for any CypD structure.

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