The production of hydrogen peroxide during early-stage protein aggregation: a common pathological mechanism in different neurodegenerative diseases?

2005 ◽  
Vol 33 (4) ◽  
pp. 548-550 ◽  
Author(s):  
B.J. Tabner ◽  
S. Turnbull ◽  
N.J. Fullwood ◽  
M. German ◽  
D. Allsop
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Early Stage ◽  
Amyloid Β ◽  
Direct Production ◽  
Esr Spin Trapping ◽  
Pathological Mechanism ◽  
Aβ Amyloid ◽  
Production Of Hydrogen ◽  
Trapping Method

By means of an ESR spin-trapping method, we have shown that Aβ (amyloid β), α-synuclein and various toxic forms of the prion protein all appear to generate H2O2in vitro. A fundamental molecular mechanism underlying the pathogenesis of cell death in several different neurodegenerative diseases could be the direct production of H2O2 during the early stages of protein aggregation.

scholarly journals Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

2006 ◽  
Vol 39 (2) ◽  
pp. 167-201 ◽  
Author(s):  
Hilal A. Lashuel ◽  
Peter T. Lansbury
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Common Mechanism ◽  
Spongiform Encephalopathy ◽  
Amyloid Fibril Formation ◽  
Amyloid Diseases

1. Introduction 22. What is the significance of the shared structural properties of disease-associated protein fibrils? 32.1 Mechanism of amyloid fibril formation in vitro 62.1.1 In vitro fibril formation involves transient population of ordered aggregates of intermediate stability, or protofibrils 63. Toxic properties of protofibrils 73.1 Protofibrils, rather than fibrils, are likely to be pathogenic 73.2 The toxic protofibril may be a mixture of related species 83.3 Morphological similarities of protofibrils suggest a common mechanism of toxicity 93.4 Are the amyloid diseases a subset of a much larger class of previously unrecognized protofibril diseases? 93.5 Fibrils, in the form of aggresomes, may function to sequester toxic protofibrils 94. Amyloid pores, a common structural link among protein aggregation neurodegenerative diseases 104.1 Mechanistic studies of amyloid fibril formation reveal common features, including pore-like protofibrils 104.1.1 Amyloid-β (Aβ) (Alzheimer's disease) 104.1.2 α-Synuclein (PD and diffuse Lewy body disease) 124.1.3 ABri (familial British dementia) 134.1.4 Superoxide dismutase-1 (amyotrophic lateral sclerosis) 134.1.5 Prion protein (Creutzfeldt–Jakob disease, bovine spongiform encephalopathy, etc.) 144.1.6 Huntingtin (Huntington's disease) 144.2 Amyloidogenic proteins that are not linked to disease also from pore-like protofibrils 154.3 Amyloid proteins form non-fibrillar aggregates that have properties of protein channels or pores 154.3.1 Aβ ‘channels’ 154.3.2 α-Synuclein ‘pores’ 164.3.3 PrP ‘channels’ 164.3.4 Polyglutamine ‘channels’ 174.4 Nature uses β-strand-mediated protein oligomerization to construct pore-forming toxins 175. Mechanisms of protofibril induced toxicity in protein aggregation diseases 195.1 The amyloid pore can explain the age-association and cell-type selectivity of the neurodegenerative diseases 195.2 Protofibrils may promote their own accumulation by inhibiting the proteasome 206. Testing the amyloid pore hypothesis by attempting to disprove it 217. Acknowledgments 228. References 22Protein fibrillization is implicated in the pathogenesis of most, if not all, age-associated neurodegenerative diseases, but the mechanism(s) by which it triggers neuronal death is unknown. Reductionist in vitro studies suggest that the amyloid protofibril may be the toxic species and that it may amplify itself by inhibiting proteasome-dependent protein degradation. Although its pathogenic target has not been identified, the properties of the protofibril suggest that neurons could be killed by unregulated membrane permeabilization, possibly by a type of protofibril referred to here as the ‘amyloid pore’. The purpose of this review is to summarize the existing supportive circumstantial evidence and to stimulate further studies designed to test the validity of this hypothesis.

scholarly journals Bacterial production and direct functional screening of expanded molecular libraries for discovering inhibitors of protein aggregation

2019 ◽  
Vol 5 (10) ◽  
pp. eaax5108 ◽  
Author(s):  
Dafni C. Delivoria ◽  
Sean Chia ◽  
Johnny Habchi ◽  
Michele Perni ◽  
Ilias Matis ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Early Stage ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Functional Screening ◽  
Parkinson’S Diseases ◽  
Aggregation Inhibitors ◽  
Molecular Libraries

Protein misfolding and aggregation are associated with a many human disorders, including Alzheimer’s and Parkinson’s diseases. Toward increasing the effectiveness of early-stage drug discovery for these conditions, we report a bacterial platform that enables the biosynthesis of molecular libraries with expanded diversities and their direct functional screening for discovering protein aggregation inhibitors. We illustrate this approach by performing, what is to our knowledge, the largest functional screen of small-size molecular entities described to date. We generated a combinatorial library of ~200 million drug-like, cyclic peptides and rapidly screened it for aggregation inhibitors against the amyloid-β peptide (Aβ42), linked to Alzheimer’s disease. Through this procedure, we identified more than 400 macrocyclic compounds that efficiently reduce Aβ42 aggregation and toxicity in vitro and in vivo. Finally, we applied a combination of deep sequencing and mutagenesis analyses to demonstrate how this system can rapidly determine structure-activity relationships and define consensus motifs required for bioactivity.

scholarly journals Emerging role of Alzheimer's disease-associated ubiquilin-1 in protein aggregation

2010 ◽  
Vol 38 (1) ◽  
pp. 150-155 ◽  
Author(s):  
Annakaisa Haapasalo ◽  
Jayashree Viswanathan ◽  
Lars Bertram ◽  
Hilkka Soininen ◽  
Rudolph E. Tanzi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Current Knowledge ◽  
Amyloid Β ◽  
Ubiquitin Proteasome System ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Abnormal Accumulation ◽  
Ad Alzheimer’S Disease

Abnormal protein aggregation and intracellular or extracellular accumulation of misfolded and aggregated proteins are key events in the pathogenesis of different neurodegenerative diseases. Furthermore, endoplasmic reticulum stress and impairment of the ubiquitin–proteasome system probably contribute to neurodegeneration in these diseases. A characteristic feature of AD (Alzheimer's disease) is the abnormal accumulation of Aβ (amyloid β-peptide) in the brain. Evidence shows that the AD-associated PS (presenilin) also forms aggregates under certain conditions and that another AD-associated protein, ubiquilin-1, controls protein aggregation and deposition of aggregated proteins. Here, we review the current knowledge of ubiquilin-1 and PS in protein aggregation and related events that potentially influence neurodegeneration.

scholarly journals Neuroinflammatory changes increase the impact of stressors on neuronal function

2009 ◽  
Vol 37 (1) ◽  
pp. 303-307 ◽  
Author(s):  
Alessia Piazza ◽  
Marina A. Lynch
Keyword(s):  
Neurodegenerative Diseases ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Experimental Conditions ◽  
Age Related ◽  
Increased Risk ◽  
Aβ Amyloid ◽  
The Impact

In the last few years, several research groups have reported that neuroinflammation is one feature common to several neurodegenerative diseases and that similar, although perhaps less profound, neuroinflammatory changes also occur with age. Age is the greatest risk factor in many neurodegenerative diseases, and the possibility exists that the underlying age-related neuroinflammation may contribute to this increased risk. Several animal models have been used to examine this possibility, and it is now accepted that, under experimental conditions in which microglial activation is up-regulated, responses to stressors are exacerbated. In the present article, these findings are discussed and data are presented from in vitro and in vivo experiments which reveal that responses to Aβ (amyloid β-peptide) are markedly up-regulated in the presence of LPS (lipopolysaccharide). These, and previous findings, point to a vulnerability associated with inflammation and suggest that, even though inflammation may not be the primary cause of neurodegenerative disease, its treatment may decelerate disease progression.

Protein aggregation, metals and oxidative stress in neurodegenerative diseases

2005 ◽  
Vol 33 (5) ◽  
pp. 1082-1086 ◽  
Author(s):  
B.J. Tabner ◽  
O.M.A. El-Agnaf ◽  
M.J. German ◽  
N.J. Fullwood ◽  
D. Allsop
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Early Stage ◽  
Redox Active ◽  
Active Metal ◽  
Future Therapy ◽  
And Oxidative Stress ◽  
Proteins And Peptides

There is clear evidence implicating oxidative stress in the pathology of many different neurodegenerative diseases. ROS (reactive oxygen species) are the primary mediators of oxidative stress and many of the aggregating proteins and peptides associated with neurodegenerative disease can generate hydrogen peroxide, a key ROS, apparently through interactions with redox-active metal ions. Our recent results suggest that ROS are generated during the very early stages of protein aggregation, when protofibrils or soluble oligomers are present, but in the absence of mature amyloid fibrils. The generation of ROS during early-stage protein aggregation may be a common, fundamental molecular mechanism underlying the pathogenesis of oxidative damage, neurodegeneration and cell death in several different neurodegenerative diseases. Drugs that specifically target this process could be useful in the future therapy of these diseases.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Insights into amyloid disease from fly models

2014 ◽  
Vol 56 ◽  
pp. 69-83 ◽  
Author(s):  
Ko-Fan Chen ◽  
Damian C. Crowther
Keyword(s):  
Drosophila Melanogaster ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Disease Pathogenesis ◽  
Amyloid Aggregates ◽  
Aβ Amyloid ◽  
Polypeptide Chains ◽  
Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

scholarly journals Observation of liquid-liquid phase separation of ataxin-3 and quantitative evaluation of its concentration in a single droplet using Raman microscopy

2021 ◽  
Author(s):  
Kazuki Murakami ◽  
Shinji Kajimoto ◽  
Daiki Shibata ◽  
Kunisato Kuroi ◽  
Fumihiko Fujii ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Quantitative Evaluation ◽  
Raman Microscopy ◽  
Liquid Phase Separation ◽  
Biological Processes ◽  
Single Droplet ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation (LLPS) plays an important role in a variety of biological processes and is also associated with protein aggregation in neurodegenerative diseases. Quantification of LLPS is necessary to...

scholarly journals Phosphoinositides signaling modulates microglial actin remodeling and phagocytosis in Alzheimer’s disease

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Smita Eknath Desale ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Signaling Pathways ◽  
Amyloid Β ◽  
Dietary Fatty Acids ◽  
Receptor Expression ◽  
Actin Binding ◽  
Actin Remodeling ◽  
Protein Deposits

AbstractAlzheimer’s disease is one of the neurodegenerative diseases, characterized by the accumulation of abnormal protein deposits, which disrupts signal transduction in neurons and other glia cells. The pathological protein in neurodegenerative diseases, Tau and amyloid-β contribute to the disrupted microglial signaling pathways, actin cytoskeleton, and cellular receptor expression. The important secondary messenger lipids i.e., phosphatidylinositols are largely affected by protein deposits of amyloid-β in Alzheimer’s disease. Phosphatidylinositols are the product of different phosphatidylinositol kinases and the state of phosphorylation at D3, D4, and D5 positions of inositol ring. Phosphatidylinositol 3,4,5-triphosphate (PI 3, 4, 5-P3) involves in phagocytic cup formation, cell polarization, whereas Phosphatidylinositol 4,5-bisphosphate (PI 4, 5-P2)-mediates the process of phagosomes formation and further its fusion with early endosome.. The necessary activation of actin-binding proteins such as Rac, WAVE complex, and ARP2/3 complex for the actin polymerization in the process of phagocytosis, migration is regulated and maintained by PI 3, 4, 5-P3 and PI 4, 5-P2. The ratio and types of fatty acid intake can influence the intracellular secondary lipid messengers along with the cellular content of phaphatidylcholine and phosphatidylethanolamine. The Amyloid-β deposits and extracellular Tau seeds disrupt phosphatidylinositides level and actin cytoskeletal network that hamper microglial-signaling pathways in AD. We hypothesize that being a lipid species intracellular levels of phosphatidylinositol would be regulated by dietary fatty acids. Further we are interested to understand phosphoinositide-based signaling cascades in phagocytosis and actin remodeling.

The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors

2021 ◽  
Author(s):  
Benjamin C Creekmore ◽  
Yi-Wei Chang ◽  
Edward B Lee
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Electron Tomography ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
X Ray Crystallography ◽  
New Information ◽  
A Cell ◽  
Regulate Protein

Abstract Neurodegenerative diseases are characterized by the accumulation of misfolded proteins. This protein aggregation suggests that abnormal proteostasis contributes to aging-related neurodegeneration. A better fundamental understanding of proteins that regulate proteostasis may provide insight into the pathophysiology of neurodegenerative disease and may perhaps reveal novel therapeutic opportunities. The 26S proteasome is the key effector of the ubiquitin-proteasome system responsible for degrading polyubiquitinated proteins. However, additional factors, such as valosin-containing protein (VCP/p97/Cdc48) and C9orf72, play a role in regulation and trafficking of substrates through the normal proteostasis systems of a cell. Nonhuman AAA+ ATPases, such as the disaggregase Hsp104, also provide insights into the biochemical processes that regulate protein aggregation. X-ray crystallography and cryo-electron microscopy (cryo-EM) structures not bound to substrate have provided meaningful information about the 26S proteasome, VCP, and Hsp104. However, recent cryo-EM structures bound to substrate have provided new information about the function and mechanism of these proteostasis factors. Cryo-EM and cryo-electron tomography data combined with biochemical data have also increased the understanding of C9orf72 and its role in maintaining proteostasis. These structural insights provide a foundation for understanding proteostasis mechanisms with near-atomic resolution upon which insights can be gleaned regarding the pathophysiology of neurodegenerative diseases.

Sign in / Sign up

Export Citation Format

Share Document