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Book ; Online ; Thesis: Entwicklung eines Vakzins für die Parkinson- Krankheit

Pesch, Verena [Verfasser] / Tamgüney, Erdem Gültekin [Gutachter] / Willbold, Dieter [Gutachter]

2024

Author's details	Verena Pesch ; Gutachter: Erdem Gültekin Tamgüney, Dieter Willbold
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	German
Publisher	Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf
Publishing place	Düsseldorf
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Conserved Signal Transduction Mechanisms and Dark Recovery Kinetic Tuning in the Pseudomonadaceae Short Light, Oxygen, Voltage (LOV) Protein Family.

Arinkin, Vladimir / Granzin, Joachim / Jaeger, Karl-Erich / Willbold, Dieter / Krauss, Ulrich / Batra-Safferling, Renu

Journal of molecular biology

2024 Volume 436, Issue 5, Page(s) 168458

Abstract: Light-Oxygen-Voltage (LOV) flavoproteins transduce a light signal into variable signaling outputs via a structural rearrangement in the sensory core domain, which is then relayed to fused effector domains via α-helical linker elements. Short LOV proteins ...

Abstract	Light-Oxygen-Voltage (LOV) flavoproteins transduce a light signal into variable signaling outputs via a structural rearrangement in the sensory core domain, which is then relayed to fused effector domains via α-helical linker elements. Short LOV proteins from Pseudomonadaceae consist of a LOV sensory core and N- and C-terminal α-helices of variable length, providing a simple model system to study the molecular mechanism of allosteric activation. Here we report the crystal structures of two LOV proteins from Pseudomonas fluorescens - SBW25-LOV in the fully light-adapted state and Pf5-LOV in the dark-state. In a comparative analysis of the Pseudomonadaceae short LOVs, the structures demonstrate light-induced rotation of the core domains and splaying of the proximal A'α and Jα helices in the N and C-termini, highlighting evidence for a conserved signal transduction mechanism. Another distinguishing feature of the Pseudomonadaceae short LOV protein family is their highly variable dark recovery, ranging from seconds to days. Understanding this variability is crucial for tuning the signaling behavior of LOV-based optogenetic tools. At 37 °C, SBW25-LOV and Pf5-LOV exhibit adduct state lifetimes of 1470 min and 3.6 min, respectively. To investigate this remarkable difference in dark recovery rates, we targeted three residues lining the solvent channel entrance to the chromophore pocket where we introduced mutations by exchanging the non-conserved amino acids from SBW25-LOV into Pf5-LOV and vice versa. Dark recovery kinetics of the resulting mutants, as well as MD simulations and solvent cavity calculations on the crystal structures suggest a correlation between solvent accessibility and adduct lifetime.
MeSH term(s)	Light ; Oxygen ; Signal Transduction ; Solvents ; Flavoproteins/chemistry ; Flavoproteins/genetics ; Flavoproteins/metabolism ; Protein Domains ; Protein Conformation, alpha-Helical ; Pseudomonas fluorescens/metabolism ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Optogenetics ; Photoreceptors, Microbial/chemistry ; Photoreceptors, Microbial/genetics ; Photoreceptors, Microbial/metabolism ; Mutation ; Crystallography, X-Ray
Chemical Substances	Oxygen (S88TT14065) ; Solvents ; Flavoproteins ; Bacterial Proteins ; Photoreceptors, Microbial
Language	English
Publishing date	2024-01-26
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2024.168458
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Article ; Online: Inhibition of Polyglutamine Misfolding with D-Enantiomeric Peptides Identified by Mirror Image Phage Display Selection.

Kolkwitz, Pauline Elisabeth / Mohrlüder, Jeannine / Willbold, Dieter

Biomolecules

2022 Volume 12, Issue 2

Abstract: Nine heritable diseases are known that are caused by unphysiologically elongated polyglutamine tracts in human proteins leading to misfolding, aggregation and neurodegeneration. Current therapeutic strategies include efforts to inhibit the expression of ... ...

Abstract	Nine heritable diseases are known that are caused by unphysiologically elongated polyglutamine tracts in human proteins leading to misfolding, aggregation and neurodegeneration. Current therapeutic strategies include efforts to inhibit the expression of the respective gene coding for the polyglutamine-containing proteins. There are, however, concerns that this may interfere with the physiological function of the respective protein. We aim to stabilize the protein's native conformation by D-enantiomeric peptide ligands to prevent misfolding and aggregation, shift the equilibrium between aggregates and monomers towards monomers and dissolve already existing aggregates into non-toxic and functional monomers. Here, we performed a mirror image phage display selection on the polyglutamine containing a fragment of the androgen receptor. An elongated polyglutamine tract in the androgen receptor causes spinal and bulbar muscular atrophy (SBMA). The selected D-enantiomeric peptides were tested for their ability to inhibit polyglutamine-induced androgen receptor aggregation. We identified D-enantiomeric peptide QF2D-2 (sqsqwstpqGkwshwprrr) as the most promising candidate. It binds to an androgen receptor fragment with 46 consecutive glutamine residues and decelerates its aggregation, even in seeded experiments. Therefore, QF2D-2 may be a promising drug candidate for SBMA treatment or even for all nine heritable polyglutamine diseases, since its aggregation-inhibiting property was shown also for a more general polyglutamine target.
MeSH term(s)	Bacteriophages/metabolism ; Humans ; Ligands ; Muscular Atrophy, Spinal/genetics ; Muscular Atrophy, Spinal/metabolism ; Peptides/chemistry
Chemical Substances	Ligands ; Peptides ; polyglutamine (26700-71-0)
Language	English
Publishing date	2022-01-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12020157
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Book ; Online ; Thesis: Adult neurogenesis and cognitive training as impact factors on the receptor architecture of the mouse olfactory system

Lothmann, Kimberley [Verfasser] / Amunts, Katrin [Gutachter] / Willbold, Dieter [Gutachter]

2023

Author's details	Kimberley Lothmann ; Gutachter: Katrin Amunts, Dieter Willbold
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Publisher	Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf
Publishing place	Düsseldorf
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Book ; Online ; Thesis: Entwicklung eines diagnostischen Assays zum Nachweis von alpha-Synuclein-Aggregaten

Schaffrath, Anja [Verfasser] / Tamgüney, Erdem Gültekin [Gutachter] / Willbold, Dieter [Gutachter]

2023

Author's details	Anja Schaffrath ; Gutachter: Erdem Gültekin Tamgüney, Dieter Willbold
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	German
Publisher	Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf
Publishing place	Düsseldorf
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Interaction of Therapeutic d-Peptides with Aβ42 Monomers, Thermodynamics, and Binding Analysis.

Leguizamon Herrera, Vivian Lorena / Buell, Alexander K / Willbold, Dieter / Barz, Bogdan

ACS chemical neuroscience

2022 Volume 13, Issue 11, Page(s) 1638–1650

Abstract: The aggregation of the amyloid-β (Aβ) peptide is a major hallmark of Alzheimer's disease. This peptide can aggregate into oligomers, proto-fibrils, and mature fibrils, which eventually assemble into amyloid plaques. The peptide monomers are the smallest ... ...

Abstract	The aggregation of the amyloid-β (Aβ) peptide is a major hallmark of Alzheimer's disease. This peptide can aggregate into oligomers, proto-fibrils, and mature fibrils, which eventually assemble into amyloid plaques. The peptide monomers are the smallest assembly units and play an important role in most of the individual processes involved in amyloid fibril formation, such as primary and secondary nucleation and elongation. Several d-peptides have been confirmed as promising candidates to inhibit the aggregation of Aβ into toxic oligomers and fibrils by specifically interacting with monomeric species. In this work, we elucidate the structural interaction and thermodynamics of binding between three d-peptides (D3, ANK6, and RD2) and Aβ42 monomers by means of enhanced molecular dynamics simulations. Our study derives thermodynamic energies in good agreement with experimental values and suggests that there is an enhanced binding for D3 and ANK6, which leads to more stable complexes than for RD2. The binding of D3 to Aβ42 is shown to be weakly exothermic and mainly entropically driven, whereas the complex formation between the ANK6 and RD2 with the Aβ42 free monomer is weakly endothermic. In addition, the changes in the solvent-accessible surface area and the radius of gyration support that the binding between Aβ42 and d-peptides is mainly driven by electrostatic and hydrophobic interactions and leads to more compact conformations.
MeSH term(s)	Alzheimer Disease/metabolism ; Amyloid/metabolism ; Amyloid beta-Peptides/metabolism ; Humans ; Molecular Dynamics Simulation ; Peptide Fragments/metabolism ; Thermodynamics
Chemical Substances	Amyloid ; Amyloid beta-Peptides ; Peptide Fragments ; amyloid beta-protein (1-42)
Language	English
Publishing date	2022-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.2c00102
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Oral Treatment with d-RD2RD2 Impedes Early Disease Mechanisms in SOD1*G93A Transgenic Mice but Does Not Prolong Survival.

Wintz, Katharina / Post, Julia / Langen, Karl-Josef / Willbold, Dieter / Willuweit, Antje / Kutzsche, Janine

Biomedicines

2023 Volume 11, Issue 4

Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, thus, progressing to complete muscle loss until the patient dies from respiratory arrest. The disease is not curable, and patients die ... ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, thus, progressing to complete muscle loss until the patient dies from respiratory arrest. The disease is not curable, and patients die approximately 2-5 years after diagnosis. Studying the underlying disease mechanisms to get access to new treatment options is, therefore, essential for patients' benefit. However, so far, only three drugs that alleviate the symptoms have been approved by the U.S. Food and Drug Administration (FDA). A new drug candidate for the treatment of ALS is the all-d-enantiomeric peptide RD2RD2. In this study, we investigated the therapeutic effect of RD2RD2 in two setups. First, we analyzed disease progression and survival in 7 week-old B6.Cg-Tg(SOD1G93A)1Gur/J mice. Second, we confirmed the result of the survival analysis in the B6SJL-Tg(SOD1G93A)1Gur/J mouse line. Shortly before disease onset, the mice were treated daily with an oral dose of 50 mg/kg body weight. Treatment with RD2RD2 led to a delayed disease onset and reduced motor phenotype as shown using the SHIRPA test, the splay reflex test, and the pole test, but did not affect survival. In conclusion, RD2RD2 has the ability to delay the onset of symptoms.
Language	English
Publishing date	2023-03-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11040995
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Article ; Online: Large dynamics of a phase separating arginine-glycine-rich domain revealed via nuclear and electron spins.

Sicoli, Giuseppe / Sieme, Daniel / Overkamp, Kerstin / Khalil, Mahdi / Backer, Robin / Griesinger, Christian / Willbold, Dieter / Rezaei-Ghaleh, Nasrollah

Nature communications

2024 Volume 15, Issue 1, Page(s) 1610

Abstract: Liquid-liquid phase separation is the key process underlying formation of membrane-less compartments in cells. A highly dynamic cellular body with rapid component exchange is Cajal body (CB), which supports the extensive compositional dynamics of the RNA ...

Abstract	Liquid-liquid phase separation is the key process underlying formation of membrane-less compartments in cells. A highly dynamic cellular body with rapid component exchange is Cajal body (CB), which supports the extensive compositional dynamics of the RNA splicing machinery, spliceosome. Here, we select an arginine-glycine (RG)-rich segment of coilin, the major component of CB, establish its RNA-induced phase separation, and through combined use of nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) probes, interrogate its dynamics within the crowded interior of formed droplets. Taking advantage of glycine-based singlet-states, we show that glycines retain a large level of sub-nanoseconds dynamics inside the coilin droplets. Furthermore, the continuous-wave (CW) and electron-electron dipolar (PELDOR) and electron-nucleus hyperfine coupling EPR data (HYSCORE) support the RNA-induced formation of dynamic coilin droplets with high coilin peptide concentrations. The combined NMR and EPR data reveal the high dynamics of the RG-rich coilin within droplets and suggest its potential role in the large dynamics of CBs.
MeSH term(s)	Nuclear Proteins/genetics ; Arginine ; Glycine ; Electrons ; RNA ; Coiled Bodies
Chemical Substances	Nuclear Proteins ; Arginine (94ZLA3W45F) ; Glycine (TE7660XO1C) ; RNA (63231-63-0)
Language	English
Publishing date	2024-02-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45788-w
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Do We Need Anti-Prion Compounds to Treat Alzheimer's Disease?

Willbold, Dieter / Kutzsche, Janine

Molecules (Basel, Switzerland)

2019 Volume 24, Issue 12

Abstract: Background: While phase III clinical trials for the treatment of Alzheimer's disease (AD) keep failing regardless of the target, more and more data suggest that the toxic protein assemblies of amyloid-beta protein (Aβ) and tubulin binding protein (TAU) ... ...

Abstract	Background: While phase III clinical trials for the treatment of Alzheimer's disease (AD) keep failing regardless of the target, more and more data suggest that the toxic protein assemblies of amyloid-beta protein (Aβ) and tubulin binding protein (TAU) behave like prions. Irrespective of the question of whether AD is theoretically or practically contagious, the presence of a self-replicating toxic etiologic agent in the brains of AD patients must have decisive consequences for drug development programs and clinical trial designs. Objectives: We intend to challenge the hypothesis that the underlying etiologic agent of AD is behaving prion-like. We want to discuss whether the outcome of clinical trials could have been predicted based on this hypothesis, and whether compounds that directly disassemble the toxic prion could be more beneficial for AD treatment. Method: We collected publicly accessible pre-clinical efficacy data of Aβ targeting compounds that failed or still are in phase III clinical trials. We describe the desired properties of an anti-prion compound and compare it the properties of past and current phase III drug candidates. Results: We could not find convincing and reproducible pre-clinical efficacy data of past and current phase III drug candidates on cognition other than in preventive treatment settings. The desired properties of an anti-Aβ-prionic compound are fulfilled by the drug candidate RD2, which has been developed to directly disassemble toxic Aβ oligomers. Conclusion: RD2 is the first anti-prion drug candidate. It is able to enhance cognition and impede neurodegeneration in three different transgenic AD mouse models, even under truly non-preventive conditions and even when applied orally. In addition, it is safe in humans.
MeSH term(s)	Alzheimer Disease/drug therapy ; Alzheimer Disease/etiology ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/antagonists & inhibitors ; Amyloid beta-Peptides/chemistry ; Amyloid beta-Peptides/metabolism ; Animals ; Clinical Trials as Topic ; Humans ; Peptides/chemistry ; Peptides/pharmacology ; Peptides/therapeutic use ; Prion Proteins/antagonists & inhibitors ; Prion Proteins/metabolism ; Protein Aggregates ; Protein Aggregation, Pathological ; Protein Multimerization ; Treatment Outcome
Chemical Substances	Amyloid beta-Peptides ; Peptides ; Prion Proteins ; Protein Aggregates
Language	English
Publishing date	2019-06-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules24122237
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Book ; Online ; Thesis: Investigation of the neurotoxic and neurodegenerative effects of engineered nanomaterials

Sofranko, Adriana [Verfasser] / Krutmann, Jean [Gutachter] / Willbold, Dieter [Gutachter]

2022

Author's details	Adriana Sofranko ; Gutachter: Jean Krutmann, Dieter Willbold
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Publisher	Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf
Publishing place	Düsseldorf
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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