scholarly journals α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jaime Santos ◽  
Pablo Gracia ◽  
Susanna Navarro ◽  
Samuel Peña-Díaz ◽  
Jordi Pujols ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Cell Damage ◽  
Biophysical Properties ◽  
Functional Protein ◽  
Guided Search ◽  
Toxic Species ◽  
High Affinity ◽  
Key Driver ◽  
The Brain ◽  
Therapeutic Avenue

Abstractα-Synuclein aggregation is a key driver of neurodegeneration in Parkinson’s disease and related syndromes. Accordingly, obtaining a molecule that targets α-synuclein toxic assemblies with high affinity is a long-pursued objective. Here, we exploit the biophysical properties of toxic oligomers and amyloid fibrils to identify a family of α-helical peptides that bind to these α-synuclein species with low nanomolar affinity, without interfering with the monomeric functional protein. This activity is translated into a high anti-aggregation potency and the ability to abrogate oligomer-induced cell damage. Using a structure-guided search we identify a human peptide expressed in the brain and the gastrointestinal tract with analogous binding, anti-aggregation, and detoxifying properties. The chemical entities we describe here may represent a therapeutic avenue for the synucleinopathies and are promising tools to assist diagnosis by discriminating between native and toxic α-synuclein species.

scholarly journals α-Helical peptidic scaffolds to target α-synuclein pathogenic species with high affinity and selectivity

2021 ◽  
Author(s):  
Jaime Santos ◽  
Pablo Gracia ◽  
Susanna Navarro ◽  
Samuel Peña-Diaz ◽  
Jordi Pujols ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Protective Role ◽  
Pathogenic Species ◽  
Biophysical Properties ◽  
Functional Protein ◽  
Helical Peptides ◽  
High Affinity ◽  
Key Driver ◽  
Function Relationship ◽  
The Brain

Abstractα-Synuclein aggregation is a key driver of neurodegeneration in Parkinson’s disease and related syndromes. Accordingly, obtaining a molecule that targets α-synuclein pathogenic assemblies with high affinity and selectivity is a long-pursued objective. Here, we have exploited the biophysical properties of toxic oligomers and amyloid fibrils to identify a family of α-helical peptides that bind selectively to these α-synuclein species with low nanomolar affinity, without interfering with the monomeric functional protein. This activity is translated into an unprecedented anti-aggregation potency and the ability to abrogate the oligomers toxicity. With a structure-function relationship in hand, we identified a human peptide expressed in the brain and in the gastrointestinal tract with exceptional binding, antiaggregation, and detoxifying properties, which suggests it might play a protective role against synucleinopathies. The chemical entities we describe here represent a new therapeutic paradigm and are promising tools to assist diagnosis by selectively detecting α-synuclein pathogenic species in biofluids.

scholarly journals Potential for imaging the high-affinity state of the 5-HT1B receptor: a comparison of three PET radioligands with differing intrinsic activity

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Anton Lindberg ◽  
Ryosuke Arakawa ◽  
Tsuyoshi Nogami ◽  
Sangram Nag ◽  
Magnus Schou ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Specific Binding ◽  
Occipital Cortex ◽  
Intrinsic Activity ◽  
High Affinity ◽  
G Protein Coupled ◽  
Dose Dependent ◽  
The Brain ◽  
Agonist Affinity States ◽  
Different Doses

Abstract Background Over the last decade, a few radioligands have been developed for PET imaging of brain 5-HT1B receptors. The 5-HT1B receptor is a G-protein-coupled receptor (GPCR) that exists in two different agonist affinity states. An agonist ligand is expected to be more sensitive towards competition from another agonist, such as endogenous 5-HT, than an antagonist ligand. It is of interest to know whether the intrinsic activity of a PET radioligand for the 5-HT1B receptor impacts on its ability to detect changes in endogenous synaptic 5-HT density. Three high-affinity 11C-labeled 5-HT1B PET radioligands with differing intrinsic activity were applied to PET measurements in cynomolgus monkey to evaluate their sensitivity to be displaced within the brain by endogenous 5-HT. For these experiments, fenfluramine was pre-administered at two different doses (1.0 and 5.0 mg/kg, i.v.) to induce synaptic 5-HT release. Results A dose-dependent response to fenfluramine was detected for all three radioligands. At the highest dose of fenfluramine (5.0 mg/kg, i.v.), reductions in specific binding in the occipital cortex increased with radioligand agonist efficacy, reaching 61% for [11C]3. The most antagonistic radioligand showed the lowest reduction in specific binding. Conclusions Three 5-HT1B PET radioligands were identified with differing intrinsic activity that could be used in imaging high- and low-affinity states of 5-HT1B receptors using PET. From this limited study, radioligand sensitivity to endogenous 5-HT appears to depend on agonist efficacy. More extensive studies are required to substantiate this suggestion.

scholarly journals Co-factor-free aggregation of tau into seeding-competent RNA-sequestering amyloid fibrils

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pijush Chakraborty ◽  
Gwladys Rivière ◽  
Shu Liu ◽  
Alain Ibáñez de Opakua ◽  
Rıza Dervişoğlu ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Corticobasal Degeneration ◽  
Binding Studies ◽  
Rigid Core ◽  
Tau Aggregation ◽  
The Brain ◽  
Tau Aggregate ◽  
Disease Specific ◽  
Tau Fibrils

AbstractPathological aggregation of the protein tau into insoluble aggregates is a hallmark of neurodegenerative diseases. The emergence of disease-specific tau aggregate structures termed tau strains, however, remains elusive. Here we show that full-length tau protein can be aggregated in the absence of co-factors into seeding-competent amyloid fibrils that sequester RNA. Using a combination of solid-state NMR spectroscopy and biochemical experiments we demonstrate that the co-factor-free amyloid fibrils of tau have a rigid core that is similar in size and location to the rigid core of tau fibrils purified from the brain of patients with corticobasal degeneration. In addition, we demonstrate that the N-terminal 30 residues of tau are immobilized during fibril formation, in agreement with the presence of an N-terminal epitope that is specifically detected by antibodies in pathological tau. Experiments in vitro and in biosensor cells further established that co-factor-free tau fibrils efficiently seed tau aggregation, while binding studies with different RNAs show that the co-factor-free tau fibrils strongly sequester RNA. Taken together the study provides a critical advance to reveal the molecular factors that guide aggregation towards disease-specific tau strains.

Dreams as an Unappreciated Therapeutic Avenue for Cognitive-Behavioral Therapists

2002 ◽  
Vol 16 (1) ◽  
pp. 29-38 ◽  
Author(s):  
Harold E. Doweiko
Keyword(s):  
Behavior Therapy ◽  
Cognitive Behavior Therapy ◽  
Cognitive Distortions ◽  
Clinical Work ◽  
Cognitive Behavior ◽  
Waking State ◽  
Dream Theory ◽  
The Brain ◽  
Therapeutic Avenue ◽  
Modern Thinking

Modern neurobiological findings demonstrate that the theaory at the heart of psychoanalysis is not viable; indeed, modern neurobiology argues that dreams are nothing more than “noise” created by the brain during the process of neuronal activation and suppression. Modern thinking, therefore, calls into question the utility of any dream theory that rests on psychoanalytic principles. Cognitive-behavior therapists can nonetheless build on contemporary neurobiological theories of dreams in their clinical work. This article argues that, while the dreaming process itself lies outside of the range of cognitive-behavior therapy, the dreamer’s recall and interpretation of the dream occurs in the normal waking state. The individual’s reported memories of the dream are therefore subject to the same cognitive distortions apparent in other dimensions of their cognitive lives.

scholarly journals Synaptic vesicle mimics affect the aggregation of wild-type and A53T α-synuclein variants differently albeit similar membrane affinity

2019 ◽  
Vol 32 (2) ◽  
pp. 59-66
Author(s):  
Sandra Rocha ◽  
Ranjeet Kumar ◽  
Istvan Horvath ◽  
Pernilla Wittung-Stafshede
Keyword(s):  
Synaptic Vesicles ◽  
Amyloid Fibrils ◽  
Membrane Surface ◽  
Amyloid Formation ◽  
Wild Type ◽  
Membrane Affinity ◽  
Axis Parallel ◽  
Biophysical Techniques ◽  
Small Unilamellar Vesicles ◽  
The Brain

Abstract α-Synuclein misfolding results in the accumulation of amyloid fibrils in Parkinson’s disease. Missense protein mutations (e.g. A53T) have been linked to early onset disease. Although α-synuclein interacts with synaptic vesicles in the brain, it is not clear what role they play in the protein aggregation process. Here, we compare the effect of small unilamellar vesicles (lipid composition similar to synaptic vesicles) on wild-type (WT) and A53T α-synuclein aggregation. Using biophysical techniques, we reveal that binding affinity to the vesicles is similar for the two proteins, and both interact with the helix long axis parallel to the membrane surface. Still, the vesicles affect the aggregation of the variants differently: effects on secondary processes such as fragmentation dominate for WT, whereas for A53T, fibril elongation is mostly affected. We speculate that vesicle interactions with aggregate intermediate species, in addition to monomer binding, vary between WT and A53T, resulting in different consequences for amyloid formation.

scholarly journals Protein Co-Aggregation Related to Amyloids: Methods of Investigation, Diversity, and Classification

2018 ◽  
Vol 19 (8) ◽  
pp. 2292 ◽  
Author(s):  
Stanislav Bondarev ◽  
Kirill Antonets ◽  
Andrey Kajava ◽  
Anton Nizhnikov ◽  
Galina Zhouravleva
Keyword(s):  
Binding Site ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Specific Binding ◽  
Protein S ◽  
Functional Protein ◽  
Functional Roles ◽  
Protein Fibrils ◽  
Protein Functions ◽  
Functional Amyloids

Amyloids are unbranched protein fibrils with a characteristic spatial structure. Although the amyloids were first described as protein deposits that are associated with the diseases, today it is becoming clear that these protein fibrils play multiple biological roles that are essential for different organisms, from archaea and bacteria to humans. The appearance of amyloid, first of all, causes changes in the intracellular quantity of the corresponding soluble protein(s), and at the same time the aggregate can include other proteins due to different molecular mechanisms. The co-aggregation may have different consequences even though usually this process leads to the depletion of a functional protein that may be associated with different diseases. The protein co-aggregation that is related to functional amyloids may mediate important biological processes and change of protein functions. In this review, we survey the known examples of the amyloid-related co-aggregation of proteins, discuss their pathogenic and functional roles, and analyze methods of their studies from bacteria and yeast to mammals. Such analysis allow for us to propose the following co-aggregation classes: (i) titration: deposition of soluble proteins on the amyloids formed by their functional partners, with such interactions mediated by a specific binding site; (ii) sequestration: interaction of amyloids with certain proteins lacking a specific binding site; (iii) axial co-aggregation of different proteins within the same amyloid fibril; and, (iv) lateral co-aggregation of amyloid fibrils, each formed by different proteins.

scholarly journals Neuroprotective Effects of Mitochondria-Targeted Plastoquinone in a Rat Model of Neonatal Hypoxic–Ischemic Brain Injury

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1871 ◽  
Author(s):  
Denis Silachev ◽  
Egor Plotnikov ◽  
Irina Pevzner ◽  
Ljubava Zorova ◽  
Anastasia Balakireva ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Targeted Delivery ◽  
Cell Damage ◽  
Brain Cell ◽  
Neuroprotective Effects ◽  
Neonatal Hypoxia ◽  
Hypoxia Ischemia ◽  
Causes Of Mortality ◽  
High Production ◽  
The Brain

Neonatal hypoxia–ischemia is one of the main causes of mortality and disability of newborns. To study the mechanisms of neonatal brain cell damage, we used a model of neonatal hypoxia–ischemia in seven-day-old rats, by annealing of the common carotid artery with subsequent hypoxia of 8% oxygen. We demonstrate that neonatal hypoxia–ischemia causes mitochondrial dysfunction associated with high production of reactive oxygen species, which leads to oxidative stress. Targeted delivery of antioxidants to the mitochondria can be an effective therapeutic approach to treat the deleterious effects of brain hypoxia–ischemia. We explored the neuroprotective properties of the mitochondria-targeted antioxidant SkQR1, which is the conjugate of a plant plastoquinone and a penetrating cation, rhodamine 19. Being introduced before or immediately after hypoxia–ischemia, SkQR1 affords neuroprotection as judged by the diminished brain damage and recovery of long-term neurological functions. Using vital sections of the brain, SkQR1 has been shown to reduce the development of oxidative stress. Thus, the mitochondrial-targeted antioxidant derived from plant plastoquinone can effectively protect the brain of newborns both in pre-ischemic and post-stroke conditions, making it a promising candidate for further clinical studies.

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