scholarly journals Vibrational Approach to the Dynamics and Structure of Protein Amyloids

Molecules ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 186 ◽  
Author(s):  
Haoqian Li ◽  
Richard Lantz ◽  
Deguo Du
Keyword(s):  
Protein Aggregation ◽  
Unnatural Amino Acids ◽  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Structural Characteristics ◽  
Conformational Dynamics ◽  
Structural Features ◽  
Protein Oligomerization ◽  
Human Pathology ◽  
Protein Misfolding And Aggregation

Amyloid diseases, including neurodegenerative diseases such as Alzheimer’s and Parkinson’s, are linked to a poorly understood progression of protein misfolding and aggregation events that culminate in tissue-selective deposition and human pathology. Elucidation of the mechanistic details of protein aggregation and the structural features of the aggregates is critical for a comprehensive understanding of the mechanisms of protein oligomerization and fibrillization. Vibrational spectroscopies, such as Fourier transform infrared (FTIR) and Raman, are powerful tools that are sensitive to the secondary structure of proteins and have been widely used to investigate protein misfolding and aggregation. We address the application of the vibrational approaches in recent studies of conformational dynamics and structural characteristics of protein oligomers and amyloid fibrils. In particular, introduction of isotope labelled carbonyl into a peptide backbone, and incorporation of the extrinsic unnatural amino acids with vibrational moieties on the side chain, have greatly expanded the ability of vibrational spectroscopy to obtain site-specific structural and dynamic information. The applications of these methods in recent studies of protein aggregation are also reviewed.

scholarly journals Suppression of Mouse AApoAII Amyloidosis Progression by Daily Supplementation with Oxidative Stress Inhibitors

2019 ◽  
Vol 2019 ◽  
pp. 1-14
Author(s):  
Jian Dai ◽  
Xin Ding ◽  
Hiroki Miyahara ◽  
Zhe Xu ◽  
Xiaoran Cui ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Treatment Strategies ◽  
Amyloid Deposition ◽  
Unfolded Protein ◽  
Antioxidative Effects ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Protein Misfolding And Aggregation

Amyloidosis is a group of diseases characterized by protein misfolding and aggregation to form amyloid fibrils and subsequent deposition within various tissues. Previous studies have indicated that amyloidosis is often associated with oxidative stress. However, it is not clear whether oxidative stress is involved in the progression of amyloidosis. We administered the oxidative stress inhibitors tempol and apocynin via drinking water to the R1.P1-Apoa2c mouse strain induced to develop mouse apolipoprotein A-II (AApoAII) amyloidosis and found that treatment with oxidative stress inhibitors led to reduction in AApoAII amyloidosis progression compared to an untreated group after 12 weeks, especially in the skin, stomach, and liver. There was no effect on ApoA-II plasma levels or expression of Apoa2 mRNA. Detection of the lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) revealed that the antioxidative effects of the treatments were most obvious in the skin, stomach, and liver, which contained higher levels of basal oxidative stress. Moreover, the unfolded protein response was reduced in the liver and was associated with a decrease in oxidative stress and amyloid deposition. These results suggest that antioxidants can suppress the progression of AApoAII amyloid deposition in the improved microenvironment of tissues and that the effect may be related to the levels of oxidative stress in local tissues. This finding provides insights for antioxidative stress treatment strategies for amyloidosis.

Novel therapeutic strategies for the treatment of protein-misfolding diseases

2007 ◽  
Vol 9 (17) ◽  
pp. 1-34 ◽  
Author(s):  
Jean-Christophe Rochet
Keyword(s):  
High Throughput Screening ◽  
Protein Misfolding ◽  
Protein Unfolding ◽  
Amyloid Fibrils ◽  
Therapeutic Strategies ◽  
Structure Based Drug Design ◽  
Human Disorders ◽  
Novel Therapeutic Strategies ◽  
And Function ◽  
Protein Misfolding And Aggregation

Most proteins in the cell adopt a compact, globular fold that determines their stability and function. Partial protein unfolding under conditions of cellular stress results in the exposure of hydrophobic regions normally buried in the interior of the native structure. Interactions involving the exposed hydrophobic surfaces of misfolded protein conformers lead to the formation of toxic aggregates, including oligomers, protofibrils and amyloid fibrils. A significant number of human disorders (e.g. Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and type II diabetes) are characterised by protein misfolding and aggregation. Over the past five years, outstanding progress has been made in the development of therapeutic strategies targeting these diseases. Three promising approaches include: (1) inhibiting protein aggregation with peptides or small molecules identified via structure-based drug design or high-throughput screening; (2) interfering with post-translational modifications that stimulate protein misfolding and aggregation; and (3) upregulating molecular chaperones or aggregate-clearance mechanisms. Ultimately, drug combinations that capitalise on more than one therapeutic strategy will constitute the most effective treatment for patients with these devastating illnesses.

Derivatizing Merocyanine Dyes to Balance Their Polarity and Viscosity Sensitivities for Protein Aggregation Detection

2021 ◽  
Author(s):  
Yulong Bai ◽  
Yanan Huang ◽  
Wang Wan ◽  
Wenhan Jin ◽  
Di Shen ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Protein Misfolding ◽  
Aggregation Process ◽  
Merocyanine Dyes ◽  
Protein Misfolding And Aggregation

Protein misfolding and aggregation process involves local polarity and viscosity fluctuation. Herein we modulated the polarity and viscosity sensitivities of merocyanine dyes to detect protein aggregation. We demonstrated how structural...

scholarly journals Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lars Plate ◽  
Christina B Cooley ◽  
John J Chen ◽  
Ryan J Paxman ◽  
Ciara M Gallagher ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Small Molecule ◽  
Protein Misfolding ◽  
Transcriptional Profiling ◽  
Extracellular Protein ◽  
Unfolded Protein ◽  
Amyloidogenic Proteins ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Protein Misfolding And Aggregation

Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. The ER reprogramming afforded by our molecules requires activation of endogenous ATF6 and occurs independent of global ER stress. Furthermore, our molecules phenocopy the ability of genetic ATF6 activation to selectively reduce secretion and extracellular aggregation of amyloidogenic proteins. These results show that small molecule-dependent ER reprogramming, achieved through preferential activation of the ATF6 transcriptional program, is a promising strategy to ameliorate imbalances in ER function associated with degenerative protein aggregation diseases.

scholarly journals Random Lasing Detection of Mutant Huntingtin Expression in Cells

Sensors ◽  
2021 ◽  
Vol 21 (11) ◽  
pp. 3825
Author(s):  
Sergio de Armas-Rillo ◽  
Felipe Fumagallo-Reading ◽  
Diego Luis-Ravelo ◽  
Beatriz Abdul-Jalbar ◽  
Tomás González-Hernández ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Cell Model ◽  
Principal Component ◽  
Structural Features ◽  
Random Lasing ◽  
Multivariate Statistical ◽  
Linear Discriminant ◽  
A Cell ◽  
Scattering Strength ◽  
Protein Misfolding And Aggregation

Huntington’s disease (HD) is an autosomal dominant, incurable neurodegenerative disease caused by mutation in the huntingtin gene (HTT). HTT mutation leads to protein misfolding and aggregation, which affect cells’ functions and structural features. Because these changes might modify the scattering strength of affected cells, we propose that random lasing (RL) is an appropriate technique for detecting cells that express mutated HTT. To explore this hypothesis, we used a cell model of HD based on the expression of two different forms—pathogenic and non-pathogenic—of HTT. The RL signals from both cell profiles were compared. A multivariate statistical analysis of the RL signals based on the principal component analysis (PCA) and linear discriminant analysis (LDA) techniques revealed substantial differences between cells that expressed the pathogenic and the non-pathogenic forms of HTT.

scholarly journals The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Oscar Aubi ◽  
Karina S. Prestegård ◽  
Kunwar Jung-KC ◽  
Tie-Jun Sten Shi ◽  
Ming Ying ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Misfolding ◽  
Phenylalanine Hydroxylase ◽  
Hepatic Tissue ◽  
Loss Of Function ◽  
Advantageous Position ◽  
Protein Misfolding And Aggregation ◽  
Activity Decrease ◽  
Systemic Accumulation ◽  
Altered Lipid

AbstractPhenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A homozygous Pah-R261Q mouse, with a highly prevalent misfolding variant in humans, reveals the expected hepatic PAH activity decrease, systemic L-Phe increase, L-tyrosine and L-tryptophan decrease, and tetrahydrobiopterin-responsive hyperphenylalaninemia. Pah-R261Q mice also present unexpected traits, including altered lipid metabolism, reduction of liver tetrahydrobiopterin content, and a metabolic profile indicative of oxidative stress. Pah-R261Q hepatic tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates of mutant PAH that colocalize with selective autophagy markers. Together, these findings reveal that PKU, customarily considered a loss-of-function disorder, can also have toxic gain-of-function contribution from protein misfolding and aggregation. The proteostasis defect and concomitant oxidative stress may explain the prevalence of comorbid conditions in adult PKU patients, placing this mouse model in an advantageous position for the discovery of mutation-specific biomarkers and therapies.

scholarly journals Temperature-Dependent Structural Variability of Prion Protein Amyloid Fibrils

2021 ◽  
Vol 22 (10) ◽  
pp. 5075
Author(s):  
Mantas Ziaunys ◽  
Andrius Sakalauskas ◽  
Kamile Mikalauskaite ◽  
Ruta Snieckute ◽  
Vytautas Smirnovas
Keyword(s):  
Protein Aggregation ◽  
Prion Protein ◽  
Amyloid Fibrils ◽  
Prion Diseases ◽  
Morphological Properties ◽  
Large Sample Size ◽  
Structural Variations ◽  
Temperature Dependent ◽  
Protein Fibrils ◽  
Propagation Properties

Prion protein aggregation into amyloid fibrils is associated with the onset and progression of prion diseases—a group of neurodegenerative amyloidoses. The process of such aggregate formation is still not fully understood, especially regarding their polymorphism, an event where the same type of protein forms multiple, conformationally and morphologically distinct structures. Considering that such structural variations can greatly complicate the search for potential antiamyloid compounds, either by having specific propagation properties or stability, it is important to better understand this aggregation event. We have recently reported the ability of prion protein fibrils to obtain at least two distinct conformations under identical conditions, which raised the question if this occurrence is tied to only certain environmental conditions. In this work, we examined a large sample size of prion protein aggregation reactions under a range of temperatures and analyzed the resulting fibril dye-binding, secondary structure and morphological properties. We show that all temperature conditions lead to the formation of more than one fibril type and that this variability may depend on the state of the initial prion protein molecules.

scholarly journals Cryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qiuye Li ◽  
W. Michael Babinchak ◽  
Witold K. Surewicz
Keyword(s):  
Amyloid Fibrils ◽  
Low Complexity ◽  
Structural Features ◽  
Protein Fragments ◽  
Hydrophobic Residues ◽  
Backbone Conformation ◽  
Hydrophobic Amino Acids ◽  
Insight Into ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis and several other neurodegenerative diseases are associated with brain deposits of amyloid-like aggregates formed by the C-terminal fragments of TDP-43 that contain the low complexity domain of the protein. Here, we report the cryo-EM structure of amyloid formed from the entire TDP-43 low complexity domain in vitro at pH 4. This structure reveals single protofilament fibrils containing a large (139-residue), tightly packed core. While the C-terminal part of this core region is largely planar and characterized by a small proportion of hydrophobic amino acids, the N-terminal region contains numerous hydrophobic residues and has a non-planar backbone conformation, resulting in rugged surfaces of fibril ends. The structural features found in these fibrils differ from those previously found for fibrils generated from short protein fragments. The present atomic model for TDP-43 LCD fibrils provides insight into potential structural perturbations caused by phosphorylation and disease-related mutations.

scholarly journals Investigating the Disordered and Membrane-Active Peptide A-Cage-C Using Conformational Ensembles

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3607
Author(s):  
Olena Dobrovolska ◽  
Øyvind Strømland ◽  
Ørjan Sele Handegård ◽  
Martin Jakubec ◽  
Morten L. Govasli ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Protein Misfolding ◽  
Driving Forces ◽  
Conformational Space ◽  
Supported Bilayers ◽  
Conformational Ensembles ◽  
Protein Membrane ◽  
Chimeric Polypeptide ◽  
Protein Misfolding And Aggregation ◽  
In Silico Analyses

The driving forces and conformational pathways leading to amphitropic protein-membrane binding and in some cases also to protein misfolding and aggregation is the subject of intensive research. In this study, a chimeric polypeptide, A-Cage-C, derived from α-Lactalbumin is investigated with the aim of elucidating conformational changes promoting interaction with bilayers. From previous studies, it is known that A-Cage-C causes membrane leakages associated with the sporadic formation of amorphous aggregates on solid-supported bilayers. Here we express and purify double-labelled A-Cage-C and prepare partially deuterated bicelles as a membrane mimicking system. We investigate A-Cage-C in the presence and absence of these bicelles at non-binding (pH 7.0) and binding (pH 4.5) conditions. Using in silico analyses, NMR, conformational clustering, and Molecular Dynamics, we provide tentative insights into the conformations of bound and unbound A-Cage-C. The conformation of each state is dynamic and samples a large amount of overlapping conformational space. We identify one of the clusters as likely representing the binding conformation and conclude tentatively that the unfolding around the central W23 segment and its reorientation may be necessary for full intercalation at binding conditions (pH 4.5). We also see evidence for an overall elongation of A-Cage-C in the presence of model bilayers.

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